Clinical Pharmacokinetics and Pharmacodynamics of Propofol

After intravenous administration, propofol is extensively bound to the plasma proteins (predominantly albumin) and erythrocytes. Any provider of anaesthesia should be trained in managing these adverse effects. However, in two large retrospective studies, Asserhøj and colleagues were unable to confirm the link between propofol and food allergies . 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 . The free aqueous concentration of propofol is thought to be reduced when it is prepared in a solution containing more medium chain triglycerides than in Intralipid®.

Propofol can be administered via a peripheral IV or central line. Propofol may be used prior to diagnostic procedures requiring anesthesia, in the management of refractory status epilepticus, and for induction or maintenance of anesthesia prior to and during surgeries. Propofol is the active component of an intravenous anesthetic formulation used for induction and maintenance of general anesthesia.

The amount of propofol excreted this way is extremely small (of the order of a few parts per billion), but the expired concentration correlates with plasma concentrations. The role of the lungs is still being debated; some studies suggest an active role of the lungs , while others do not , or state that the lungs are merely a temporary propofol reservoir and later release propofol from binding sites back into circulation . Extrahepatic sites of metabolism account for 40% of total propofol clearance, which has been confirmed during studies of propofol metabolism during the anhepatic stage of liver transplantation . The mean clearance of propofol is around 2.2 L/min , which is higher than the total liver blood flow. Because of this efficiency, propofol metabolism depends critically on maintained hepatic perfusion, and any decreases in hepatic blood flow 4rabet com concomitantly decrease the propofol metabolic rate.

In healthy adults younger than 55 years of age, the Diprivan® package insert advises an induction dose of 2–2.5 mg/kg, administered in boluses of 40 mg every 10 s, titrated to the onset of hypnotic effect, and a maintenance dose of 6–12 mg/kg/h. Multiple propofol dosing schemes exist; however, due to considerable variability in the propofol dose necessary to achieve certain clinical endpoints, these should only be regarded as very approximate dosing guidelines. Propofol is used for the induction and maintenance of the hypnotic component of sedation or general anaesthesia. Although this reformulation of propofol has reduced the prevalence of pain on injection during the induction of anaesthesia, it still remains a problem in clinical practice . Response surface modelling provides a tool to gain understanding and explore these complex interactions. 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.

Fentanyl significantly decreases the propofol concentration required for loss of consciousness and suppression of responses to noxious stimuli . This additive interaction is not surprising as Sebel et al. demonstrated that propofol and sevoflurane have separate binding sites but converging pathways of action on the GABAα receptor 181, 182. 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. This discrepancy might be due to study methodologies involving inaccurate PK models, or data collection in a non-steady state. The interaction can also be modelled using a response surface modelling technique .

Central Nervous System

Although our understanding of the actions of propofol at the molecular level is quite extensive, we do not entirely understand how these molecular effects translate into alterations in cellular, synaptic and neural network function, and in turn cause unconsciousness . At low concentrations, propofol potentiates GABA-activated inward chloride currents, while at higher concentrations, it directly activates the channel opening . Propofol exerts its hypnotic effect through potentiation of the effects of the inhibitory neurotransmitter GABA . The prediction accuracy and bias are comparable with that of the major compartmental models . It incorporates submodels for the lung and brain, and a less detailed ‘lumped model’ for the rest of the body. The physiologically-based hybrid recirculatory model published by Upton and Ludbrook is an example of a PBPK propofol model.

propofol

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.

• Recently, the use of allometric scaling of model components to the size descriptor has become more popular .
• Other adverse effects are cardiovascular (bradycardia, hypotension) and metabolic (hyperlipidaemia secondary to infusion of lipid formulation) .
• 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.
• Also tell them if you smoke, drink alcohol, or use illegal drugs.
• Any provider of anaesthesia should be trained in managing these adverse effects.

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.

Like most anaesthetics, propofol is a γ-aminobutyric acid (GABA) receptor agonist. The main adverse effects are disturbances in cardiopulmonary physiology. With subsequent reformulation of propofol into an oil-based emulsion, giving it a milky appearance, this challenge was overcome, and propofol gained widespread use as a key anesthetic agent. Talk to your doctor about the risks of giving this medication to young children.

The study findings range from an additive to synergistic interaction 165–171. In vitro studies demonstrate this possibility, however the results are not directly transposable to the in vivo situation . Drugs that decrease cardiac output and cause a concomitant decrease in hepatic perfusion alter the distribution and metabolism of propofol, e.g. esmolol and in propofol itself 158, 159