Pharmacokinetics ketamine

Williams and Wainer (2002) use examples of two chiral separations to demonstrate their utility in research. In one example, the difference between enantiomers in the competitive displacement of cyclosporine from immobilized P-glycoprotein was studied. In the other, the pharmacokinetic profiles of (+) and (—)-ketamine and (-h) and (—)-norketamine were determined (Williams and Wainer, 2002). 

Several general anesthetics (isoflurane, ketamine, thiopental, etomidate) have one or more chiral carbons and thus exist as pairs ot stereoisomers. In many cases one stereoisomer is more potent than the other at providing anesthesia despite little difference in pharmacokinetics (Christensen Lee, 1973 Benthuysen et ak, 1989 Harris et ak, 1992 Dickinson et ak, 1994). The stereoisomers have equal hydrophobic properties and partition equally into the membrane. 

Figure 2.6. Percent of reduction in EEG median frequency as function of ketamine plasma concentration given as the two enatiomeric forms. (Reprinted with permission from Rowland and Tozer, Clinical Pharmacokinetics, 3rd ed., Lea Febiger, Philadelphia, 1995, p. 341.)...

Prior use of benzodiazepines or opiates limits the psychotomimetic effects of ketamine. There has been a double-blind, placebo-controlled study of the role of lorazepam in reducing these effects after subanesthetic doses of ketamine in 23 volunteers who received lorazepam 2 mg or placebo, 2 hours before either a bolus dose of ketamine 0.26 mg/kg followed by an infusion of 0.65 mg/kg/hour or a placebo infusion (438). The ability of lorazepam to block the undesirable effects of ketamine was limited to just some effects. It reduced the ketamine-associated emotional distress and perceptual alterations, but exacerbated the sedative, attention-impairing, and amnesic effects of ketamine. However, it failed to reduce many of the cognitive and behavioral effects of ketamine. There were no pharmacokinetic interactions between subanesthetic doses of ketamine and lorazepam. 

Currently there is a trend toward the synthesis and large-scale production of a single active enantiomer in the pharmaceutical industry [61-63]. In addition, in some cases a racemic drug formulation may contain an enantiomer that will be more potent (pharmacologically active) than the other enantiomer(s). For example, carvedilol, a drug that interacts with adrenoceptors, has one chiral center yielding two enantiomers. The (-)-enantiomer is a potent beta-receptor blocker while the (-i-)-enantiomer is about 100-fold weaker at the beta-receptor. Ketamine is an intravenous anesthetic where the (+)-enantiomer is more potent and less toxic than the (-)-enantiomer. Furthermore, the possibility of in vivo chiral inversion—that is, prochiral chiral, chiral nonchiral, chiral diastereoisomer, and chiral chiral transformations—could create critical issues in the interpretation of the metabolism and pharmacokinetics of the drug. Therefore, selective analytical methods for separations of enantionmers and diastereomers, where applicable, are inherently important. 

The pharmacokinetic parameters for propofol in the horse are derived from a study of propofol and ketamine constant rate infusion (Nolan et al... 

Artru A A 1990 Hypocapnia and diazepam reverse and midazolam or fentanyl attenuates ketamine induced Increase of cerebral blood volume and/or cerebrospinal fluid pressure. In Domino E F (ed) Status of ketamine in anesthesiology. NPP Books, Ann Arbor, Ml, p. 119 Aurich C, Aurich J E, Klug E 1993 Naloxone affects gastrointestinal functions and behaviour in horses. Deutsche Tierarztiiche Wochenschrift 100 314-315 Ballard S, Shults T, Kownacki A A et al 1982 The pharmacokinetics, pharmacological responses and behavioral effects of acepromazine in the horse. 

Bennett R C, Steffey E P 2002 Use of opioids for pain and anesthetic management in horses. Veterinary Clinics of North America Equine Practice 18 47-60 Bennett R C, Taylor P M, Brearley J C et al 1998 Comparison of detomidine/ketamine and guaiphenesin/thiopentone for induction of anaesthesia in horses maintained with halothane. Veterinary Record 142 541-545 Bettschart-Wolfensberger R, Clarke K W, Vainio O et al 1999 Pharmacokinetics of medetomidine in ponies and elaboration of a medetomidine infusion regime which provides a constant level of sedation. Research in Veterinary Science 67 41-46 Bettschart-Wolfensberger R, Freeman S L. Jaggin-... 

Kaka J S, Klavano P A, Hayton W L 1979 Pharmacokinetics of ketamine in the horse. American Journal of Veterinary Research 40 978-981... 

American Journal of Veterinary Research 61 1579-1586 Nolan A, Reid J, Welsh E et al 1996 Simultaneous infusions of propofol and ketamine in ponies premedicated with detomidine a pharmacokinetic study. Research in Veterinary Science 60 262-266 Norman W M, Court M H, Greenblatt D J 1997 Age-related changes in the pharmacokinetic disposition of diazepam in foals. American Journal of Veterinary Research 58 878-880... 

Wan P Y, Trim C M, Mueller P O 1992 Xylazine-ketamine and detomidine-tiletamine-zolazepam anesthesia in horses. Veterinary Surgery 21 312-318 Waterman A E, Amin A 1992 The influence of surgery and anaesthesia on the pharmacokinetics of pethidine in the horse. Equine Veterinary Journai Suppiement 11 56-58 Waterman A E, Robertson S A, Lane J G 1987 Pharmacokinetics of intravenously administered ketamine in the horse. Research in Veterinary Science 42 162-166... 

Table 3.11 Pharmacokinetic parameters showing the influence of xylazine premedication (0.2 mg/kg, i.m.) on the disposition of ketamine (5 mg/kg, i.v.) and the duration of anaesthesia in female ruminant calves. Results are expressed as mean + SEM n = 4.

Pharmacokinetic parameter Ketamine Xylazine + ketamine Significance3... 

Waterman, A.E. (1984) The pharmacokinetics of ketamine administered intravenously in calves and the modifying effect of premedication with xylazine hydrochloride. Journal of Veterinary Pharmacology and Therapeutics, 7, 125-130. 

In addition to pharmacokinetic drug-drug interactions, pharmacodynamic effects have been reported as well. Halothane increases the susceptibility to ventricular arrhythmias under theophylline therapy as a result of increased sensitivity of the myocardium to endogenous catecholamine release by theophylUne. Ketamine lowers the theophyUine seizure threshold. Benzodiazepines Uke midazolam, diazepam, lorazepam, and Uurazepam increase the central nervous system concentration of adenosine, a potent central nervous system depressant. As theophyUine also blocks adenosine receptors, it counteracts benzodiazepine-induced sedation, resulting in increased dosage requirements for these compounds. ... 

B. Pharmacokinetics. PCP is rapidly absorbed by inhalation or ingestion. The volume of distribution (Vd) is about 6 L/kg. The duration of clinical effects after an overdose is highly variable and ranges from 11-14 hours in one report to 1-4 days in another. PCP is eliminated mainly by hepatic metabolism, although renal and gastric excretion account for a small fraction and are pH dependent. (See also Table 11-59.) Ketamine is well absorbed after snorting, in-... 

Geisslinger, G. Hering, W. Thomann, P. Knoll, R. Kamp, H.D. Brune, K. Pharmacokinetics and pharmacodynamics of ketamine enantiomers in surgical patients using a stereoselective analytical method. Br. J. Anaesth. 1993, 70, 666 71. 

The hi-dose delivery system for our intransal ketamine product candidate provides non-invasive (i.e. needle-free) administration compared to IV or IM injections, via a rugged, simple to use device that can be patient-administered if necessary. Each disposable device delivers a total of 30 mg ketamine with well-characterized, predictable pharmacokinetics. This approach to delivering subanesthetic doses of ketamine may be particularly advantageous in emergency situations where convenience, speed of drug delivery/onset, and avoidance of accidental needle sticks in healthcare providers are desirable. In addition, our intranasal ketamine product candidate was formulated to minimize neurotoxicity, a question that has been raised regarding the differently formulated ketamine product currently approved for anesthesia. 

Peltoniemi M A, Saari Tl, Hagelberg NM, Laine K, Kurkinen KJ, Neuvonen PJ, et al. Rifempicin has a profoimd effect on the pharmacokinetics of oral S-ketamine and less on intravenous S-ketamine. Basic CUn Pharmacol Toxicol 2012 111 325-32. 

---