NEW INTRAVENOUS ANESTHETICS - REMIFENTANI L, S(-KETAMINE, ELTANOLONE AND TARGET CONTROLLED INFUSION())

The need for better anaesthetic agents has led to the approval or the clinical studies of new compounds, which have or are assumed to have a higher degree of controllability or an improved spectrum of undesired side effects compared to other approved anaesthetics. For the i.v.-an aesthetics, different approaches have been used to achieve this. Among these are the new synthesis of a new chemical entity (NCE), the isola tion of an isomer of a racemic mixture and the new galenic preparation of a known substance for i.v.-application. This review gives for all three approaches an example. Remifentanil is a NCE which has been rele ased in Germany a few months ago. This compound has reached the highes t degree of intraoperative controllability among all i.v. anaesthetics . Its context-sensitive half-life, that is the effective time for drug concentration to decline by 50% (ET(50)), is about 3-4 min even after several hours of continuous administration. One reason for this excep tional property is that its metabolism is independent of liver and kid ney function and depends almost only on blood and tissue nonspecific e sterases. S(+)-ketamine represents an example for the isolation of a s pecific isomer out of a known racemic mixture. Racemic ketamine was in troduced into clinical practice in 1965. The clinical trials with the isolated S(+)-ketamine, which are finished now, showed that the racemi c mixture of both isomer does not lead to an additive effect, but the action of S(+)-ketamine is weakened by the R(-)-compound. In volunteer s studies it was not possible to achieve a complete loss of consciousn ess by administration of R(-) ketamine only, whereby with S(+)-ketamin e one could reduce the dose with respect to the racemic mixture by a f actor of two to achieve complete consciousness. This dose reduction is accompanied by a faster offset time. For broader clinical application s one would therefore expect a higher degree of controllability and a shortened recovery period. With eltanolon a substance is presented whi ch is known as the metabolite pregnanolon of the reductive metabolic p athway of progesterone since the 50s and which is known to possess str ong hypnotic potency. However, because of its low water solubility it could not be studied as an i.v. agent until in 1990 one succeeded in m aking a water soluable emulsion in fat. The clearance of eltanolon is ca. 25 ml/kg/min and it has a terminal half-life of about 3 hr. It has , however, a pronounced hystensis of 8 min between blood and effect si te. This unfavourable pharmacokinetic property in conjunction with obs erved unvoluntary spontaneous movements and increased muscle tone duri ng application has led to the cessation of its further clinical develo pment. With the introduction of shorter acting compounds it is also ne cessary to improve the traditional techniques of i.v. drug delivery li ke manual bolus injections or drip infusions. After more than 16 years of research and development in the field of Target-Controlled Infusio ns (TCI), there has been recently introduced the so called Diprifusor- TCI, as a commercially availabe software module to control the deliver y of propofol. TCI uses established pharmacokinetic data to determine infusion rates to achieve desired drug concentrations serving as the t arget, which can be chosen interactively. This way of dosing i.v. anes thetics is obviously not restricted to one specific compound but can b e applied to any i.v.-drug if appropriate pharmacokinetic data are use d.