Remifentanil pharmacokinetics

Remifentanil, recently approved for use in the United States and Europe, is the first truly ultra-shortacting opioid. Remifentanil s uifique ester linkage allows it to be rapidly degraded to an inactive carboxylic acid metabolite by nonspecific esterases found in tissue and red blood cells. Since it is not a good substrate for plasma pseudocholinesterase, deficiency of the enzyme does not influence its duration of action. Also, hepatic and renal insufficiencies do not influence remifentanil s pharmacokinetics, so it is useful when liver or kidney failure is a factor. Because of its rapid clearance following infusion, remifentanil has gained popularity as an agent for maintenance of anesthesia when an IV technique is practical. 

Figure 7.6 Structure of remifentanil and its major metabolite formed by ester hydrolysis. contrast, alfentanil has an intermediate hepatic extraction (0.3-0.5) and alfentanil clearance will be sensitive to changes in both liver blood flow and reduced enzyme capacity in patients with liver disease. Although the kidneys play a minor role in the elimination of most opioids, renal disease can influence their pharmacokinetic profile, secondary to alterations in plasma proteins and intra- and extravascular volumes. Neither the pharmacokinetics nor the pharmacodynamics of remifentanil is significantly altered in patients with liver or renal disease.

Pharmacokinetic properties Remifentanil is an ultra-short acting compound (Michelsen and Hug, 1996), rapidly inactivated by plasma and tissue esterases. The terminal elimination half-life is 10-20 min. 

Remifentanil by infnsion (n = 49) has been compared with titrated bolnses of pethidine (n = 51) in a randomized, donble-blind stndy in 100 patients undergoing outpatient colonoscopy (9). The incidences of tachycardia, hypotension, and nausea were significantly less with remifentanil than with pethidine, but there were higher anxiety and pain scores with remifentanil. However, the study was a comparison of two opioids with different pharmacokinetic profiles, which makes it very difficult to achieve equipotent doses for the purpose of comparison. 

T. D. Egan, H. J. Lemmens, P. Eiset, D. J. Hermann, K. T. Mnir, D. R. Stanski, and S. L. Shafer, The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 79 881-892 (1993). 

FIGURE 31.5 Pharmacokinetics and EEG pharmacodynamics following a short infusion of remifentanil. 

In the case of remifentanil it was also proved that, as predicted by the basic principles used in soft drug design, the possibility of drug interactions could be minimized by building metabolic considerations into the structure. Clearance, volume of distribution, and terminal half-life data indicated that coadministration of esmolol has no significant (P < 0.05) effect on the pharmacokinetics (or pharmacodynamics) of remifentanil in rats, despite both drugs being metabolized by nonspecific esterases (99,100). 

Ludbrook GL, Upton RN. Pharmacokinetic drug interaction between propofol and remifentanil (2003) 97, 924-5. 

Bouillon T, Bruhn J, Radu-Radulescu L, Bertaccini E, Park S, Shafer S. Ncn-stea(ty state analysis of the pharmacokinetic interaction between propofol and remifentanil Anes siol-ogy (2002) 97, 1350-62. 

Remifentanil is rapidly and extensively metabolized by nonspecific blood and tissue esterases (but not plasma cholinesterase) to a carboxylic acid derivative that is 4600 times less active than the parent compound [2]. Approximately 95% of remifentanil is excreted in the urine as this metabolite. It follows that the pharmacokinetics of remifentanil are not significantly changed in patients with renal impairment. The clearance of the carboxylic acid metabolite is reduced with renal dysfunction however, there is no demonstrated clinical relevance of the accumulated metabolite. The pharmacokinetics are also unchanged in patients with severe hepatic impairment (even those awaiting liver transplant. 

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