Clinical Pharmacokinetics and Pharmacodynamics of Propofol

Therefore, some manufacturers produced and sold generic propofol formulations, such as Propoven® (Fresenius-Kabi, Bad Homburg, Germany) and Propofol-Lipuro® (B-Braun, Melsungen, Germany), containing more medium and fewer long chain-length fatty acids . A number of different formulations of propofol are currently available, produced by many different manufacturers. It is formulated as an Intralipid®-based emulsion (Fresenuis Kabi, Bad Homburg, Germany) and thus contains the same ingredients, namely soybean oil (100 mg/mL), glycerol (22.5 mg/mL), and egg lecithin (12 mg/mL), and of course propofol as the active ingredient . The Diprivan® (AstraZeneca, London, UK) formulation of propofol came on to the market in 1989 in the US and is still available today worldwide.

Liver is very efficient at propofol metabolism, with a blood extraction ratio of 90%. The context-sensitive decrement time for propofol is thus generally favourable compared with other hypnotics. The speed of induction depends on patient-related factors (cardiac output being one of the most important factors) and speed of infusion. Propofol readily crosses the blood–brain barrier (BBB) and causes rapid loss of consciousness (sometimes within the time it takes for a drug to pass through the circulation once ).

Neurophysiological Effects

• It is formulated as an Intralipid®-based emulsion (Fresenuis Kabi, Bad Homburg, Germany) and thus contains the same ingredients, namely soybean oil (100 mg/mL), glycerol (22.5 mg/mL), and egg lecithin (12 mg/mL), and of course propofol as the active ingredient .
• Propofol administration should always be titrated according to clinical effect, which is part of the reason why the clinician should closely monitor the effects and adverse effects of propofol (vide infra).
• Propofol administration also results in decreased cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure.
• Its use can avoid the need for paralysis and in some instances the potential side-effects of succinylcholine.
• PRIS occurs mostly in the setting of prolonged and high-dose propofol infusion administration in children.
• The majority of propofol (70%) is conjugated to propofol glucuronide by uridine 5′-diphosphate (UDP) glucuronosyltransferase.

In adults, a loading dose of 0.1 μg kg−1 administered during a 10-min period reduced the half maximal effective concentration (EC50) of propofol for successful i-gel (Intersurgical, Berkshire, UK) airway insertion from 6.75 to 3.18 µg/mL ; a comparable effect was not found in children . When administered preoperatively, dexmedetomidine reduced the propofol dose necessary for sedation and induction of anaesthesia 172, 173. As with many other drugs used in anaesthesia 160, 161, concomitant administration of propofol with other drugs dependent on metabolism by CYP could interfere with its metabolism. Alterations in the PD (clinically visible) drug dose–effect relationship can be secondary to PK and/or PD interactions; therefore, these interactions are most often not discussed separately when considering clinical applications. This has been demonstrated in mice and in patients undergoing propofol sedation while undergoing surgical procedures under regional anaesthesia .

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.

Hypnotic Effects

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

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Multiple studies have investigated its effect on the propofol concentration necessary to reach specific clinical endpoints. This combined effectiveness can be explored in an isobolographic analysis using isoboles (or ‘iso-effective’ drug effect dose curves) to show all the dose combinations of drugs resulting in the same clinical effect . In order to mathematically delineate the interaction between different drugs, their combined effectiveness to reach a certain clinically relevant endpoint is assessed. Nonetheless, care should be taken when infusing propofol with other drugs.

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.

Although propofol is well-established in clinical practice, there have been a number of studies published in recent years on the clinical use and pharmacology of the drug. Its efficacy and utility has also been proven for sedation of patients in the intensive care unit (ICU) and conscious sedation of patients undergoing diagnostic or invasive procedures . It is used for sedation and anaesthesia for almost all types of surgery, but is particularly well-suited for 4rabet game anaesthesia in patients undergoing ambulatory and neurosurgery where rapid psychomotor recovery are of upmost importance. Visual displays illustrating the effect of these interactions in real time can aid clinicians in optimal drug dosing while minimizing adverse effects.

A recently published meta-analysis comparing postoperative pain after propofol versus inhalation-based anaesthesia did not demonstrate any significant differences, mainly because of substantial heterogeneity among studies published to date . The amnestic effects of propofol do not seem to be caused by interference with memory encoding, but a low-dose of propofol has been shown to induce amnesia without any impairments in behaviour . Finally, the cerebral cortex has long been identified as an important drug effect target for hypnotic drugs. The function of the thalamus as a critical sensory information relay from subcortical structures to the cortex could be impeded by hypnotic drugs , although thalamic depression seen after loss of consciousness could merely reflect the decrease in global cortical activity .