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In the Marsh model, the volumes (V1, V2, V3) are a linear function of patient weight, while the intercompartmental transfer rates (k12, k21, k13, k31) are constant. Although the different models have a similar structure, there are differences in the number of covariates, and in scaling of the volumes and/or clearances in relation to these covariates (see Tables 1 and 2 for study methods and model equations derived from different models). For highly lipophilic drugs, the best size descriptor of volume is probably total body weight (TBW), or another descriptor that incorporates fat mass, while the best size descriptor for clearance is fat free mass . A PK model is a mathematical means of describing the PK behaviour (distribution and clearance) of a particular drug in the body. Most of the older studies of the PK of propofol determined only the noncompartmental PK parameters to characterize the PK of propofol. Online estimations of propofol plasma concentration, using measurement of expired concentrations, is thus challenging but feasible 45–47.
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.
By incorporation of an azobenzene unit, a photoswitchable version of propofol (AP2) was developed in 2012 that allows for optical control of GABAA receptors with light. Marketed as Lusedra, this formulation may not produce the pain at the injection site that often occurs with the conventional form of the drug. Fospropofol is rapidly broken down by the enzyme alkaline phosphatase to form propofol. However, due to anaphylactic reactions to cremophor, this formulation was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil and propofol mixture in water. The half-life of elimination of propofol has been estimated to be between 2 and 24 hours. By contrast, there is a high incidence of postoperative nausea and vomiting after administration of volatile anesthetics, which contribute to a 4rabet official significant decrease in the whole-brain content of AEA that can last up to forty minutes after induction.
Indications, Contraindications, Drug Dosing Regimen and Adverse Effects
The most simple compartmental model contains one compartment and two model parameters, namely the volume of distribution (Vd) and clearance. After metabolism, 88% of propofol is excreted within 5 days in the urine. They have an extraction ratio of 60–70% 40, 41 and account for up to one-third of total propofol metabolism. Propofol metabolites are subsequently conjugated to form 4-(2,6-diisopropyl-1,4-quinol)-sulphate, 1-(2,6-diisopropyl-1,4-quinol)-glucuronide and 4-(2,6-diisopropyl-1,4-quinol)-glucuronide 37, 38 (for a graphic representation of the metabolic pathway of propofol see Fig. 1). Environmental and genetic influences on the CYP2B6 can, at least partially, explain the interindividual variability in hydroxylation of propofol in liver microsomes .
Routine procedural sedation
- For propofol, the main clinical effect is loss of consciousness, which is difficult to quantify.
- 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.
- Dexmedetomidine reduced propofol use during spinal surgery under propofol–remifentanil anaesthesia, and prolonged recovery times at the end of propofol anaesthesia if it was not stopped early 176, 177.
- Despite the fact that the liver and kidneys are extensively involved in metabolism and excretion of propofol, their function does not appear to be affected by propofol.
- Propofol, anesthetic drug used to induce and maintain general anesthesia and to sedate patients for certain medical procedures.
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.
As a result, Eleveld et al. were able to identify a few, clinically very relevant, correlations. First published in 2014, the PK model was recently expanded with a PD analysis . In other words, they scaled the volumes and clearances in the model to a power exponent (between 0.73 and 1.1), which allowed them to more realistically estimate the volumes and clearances in a wide range of different bodyweights, from a small rat weighing 0.25 kg to an adult weighing 93 kg. They concomitantly demonstrated that scaling of model compartments and clearances to power exponents (between 0.55 and 0.75) of normalized TBW yielded better model predictions than that of linear scaling. As soon as these begin to diverge, model predictions can be erroneous. As a result, commercially available TCI devices programmed with the Schnider model do not allow the user to input parameters that generate BMI values above these limits.
Mild myoclonic movements are common, as with other intravenous hypnotic agents. Possibly as the result of depression of the central inspiratory drive, propofol may produce significant decreases in respiratory rate, minute volume, tidal volume, mean inspiratory flow rate, and functional residual capacity. As a respiratory depressant, propofol frequently produces apnea.
Originally developed as ICI 35868, propofol was chosen after extensive evaluation and structure–activity relationship studies of the anesthetic potencies and pharmacokinetic profiles of a series of ortho-alkylated phenols. John B. Glen, a veterinarian and researcher at Imperial Chemical Industries (ICI), spent thirteen years developing propofol, an effort for which he was awarded the 2018 Lasker Award for clinical research. However, its duration of clinical effect is much shorter, because propofol is rapidly distributed into peripheral tissues. At high doses, propofol may activate GABAA receptors in the absence of GABA, behaving as a GABAA receptor agonist as well. The respiratory effects of propofol are increased if given with other respiratory depressants, including benzodiazepines. Propofol is also reported to induce priapism in some individuals, and has been observed to suppress REM sleep and to worsen the poor sleep quality in some patients.