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It belongs to the particularities of anaesthesia that the conscious response of the patient to drug therapy is not available for the adjustment of drug therapy and that the side-effects of anaesthetic drug therapy would be in general lethal if no special measures were taken such as artificial ventilation. Both conditions do not allow for a slow, time-consuming titration of drug effect towards the therapeutically effective window, but measures have to be taken to reach a therapeutic target fast (within seconds to a few minutes), reliably, and with precision. Integrated pharmacokinetic-pharmacodynamic models have proved to be a useful mathematical framework to institute such drug delivery to patients. The theory of model-based interactive drug dosing on the basis of common pharmacokinetic-pharmacodynamic (pk-pd) models is outlined and the target-controlled infusion system (TCI) is presented as a new anaesthetic dosing technique that has developed during the last decade. Whereas TCI presents an open-loop dosing strategy (the past output does not influence the future input), current research deals with the model-based adaptive closed-loop administration of anaesthetics. In these systems the past output is used to adapt and individualize the initial pk-pd model to the patients and thus has an influence on future drug dosing which is based on the adapted model. [ABSTRACT FROM AUTHOR]

Propofol (2,6-diisopropylphenol) is inadequably soluble in water and is therefore formulated as a lipid emulsion. This may have disadvantages when propofol is used to provide total intravenous anaesthesia or especially during long-term sedation. There has been considerable interest in the development of new propofol formulations or propofol prodrugs. GPI 15715 or fospropofol (Aquavan injection; Guilford Pharmaceutical, Baltimore, MD) is the first water-soluble prodrug that has been thoroughly studied in human volunteers and patients. GPI 15751 or fospropofol is cleaved by alkaline phosphatase to phosphate, formaldehyde and propofol. Formaldehyde is rapidly metabolised to formate. Although a formate accumulation is the principal pathomechanism responsible for the toxicity of methanol ingestion, so far there has been no report of toxicity due to the administration of fospropofol or other phosphate ester prodrugs, such as fosphenytoin. Fosphenytoin has been successfully introduced into the market for the treatment of status epilepticus in 1996. The main side-effects were a feeling of paraesthesia after rapid i.v. administration of GPI 15715 or fospropofol, which has also been described for fosphenytoin. The pharmacokinetics of GPI 15715 or fospropofol could be described by a combined pharmacokinetic model with a submodel of two compartments for GPI 15715 and of three compartments for propofolG. The liberated propofolG compared to lipid-formulated propofol showed unexpected pharmacokinetic and pharmacodynamic differences. We found a significantly greater Vc, Vdss, significantly shorter α- and β-half-life and a longer MRT (mean residence time) for propofolG. The pharmacodynamic potency of propofolG appears to be higher than propofol when measured by EEG and clinical signs of hypnosis. In summary, GPI 15715 or fospropofol was well suited to provide anaesthesia or conscious sedation. [ABSTRACT FROM AUTHOR]