Pharmacokinetics and Pharmacodynamics of Sedatives and Analgesics in the Treatment of Agitated Critically Ill Patients

Abstract

The pharmacokinetics and pharmacodynamics of sedatives and analgesics are significantly altered in the critically ill. These changes may account for the large differences in drug dosage requirements compared with other patient populations. Drugs that in other settings may be considered short-acting often have significantly altered onset and duration of action in critically ill patients, necessitating a change in dosage. Of the benzodiazepines, lorazepam is the drug whose parameters are the least likely to be altered in critical illness. The presence of active metabolites with other benzodiazepines complicates their use during periods of prolonged use. Similarly, the presence of active metabolites of morphine and pethidine (meperidine) warrants caution in patients with renal insufficiency. The fewer cardiovascular effects seen with high-potency opioids, such as fentanyl and sufentanil, increase their usefulness in haemodynamically compromised patients. The pharmacodynamics of propofol are not significantly altered in the critically ill. Ketamine should be used with a benzodiazepine to prevent the emergence of psychomimetic reactions. Lower sedative doses of benzodiazepines and anaesthetics may not provide reliable amnesia. Barbiturates and propofol probably do not induce hyperalgesia and lack intrinsic analgesic activity. The antipsychotic agent haloperidol has a calming effect on patients and administration to the point of sedation is generally not necessary. Combinations of sedatives and analgesics are synergistic in producing sedation. The costs of sedation and analgesia are very variable and closely linked to the pharmacokinetics and pharmacodynamics of the drug. Monitoring of sedation and analgesia is difficult in uncooperative patients in the intensive care unit. In the future, specific monitoring tools may assist clinicians in the regulation of infusions of sedative and analgesic agents.

Effects of Protein Calorie Malnutrition on the Pharmacokinetics of Ketamine in Rats

“…However, the volume of distribution of racemic KET reported in the literature for species other than rat is approximately 3 l/kg (Kaka and Hayton, 1980;Domino et al, 1982, and references therein). A species difference in plasma protein or tissue binding could lead to such an effect, although KET has been found to exhibit very low protein binding (Duvaldestin, 1981;Wagner and O'Hara, 1997).…”

Functional recovery after neuromuscular blockade in mechanically ventilated critically ill patients

“…The half-life of midazolam, lorazepam, haloperidol, and propofol ranges from 3 to 11, 8 to 15, 18 to 54, and 26 to 32 hours, respectively. 11 However, no published reports were found describing delayed recovery after any of these medications that mimic the prolonged recovery effects of NMBAs. In contrast, benzodiazepines sometimes induce paradoxic agitation with excessive muscle activity, rather than severe weakness and inactivity.…”

Mechanisms Involved in the Antiplatelet Activity of Ketamine in Human Platelets

“…This inhibitory effect of ketamine was demonstrable with the use of various agonists: collagen, epinephrine, and ADP. Analgesia occurs when concentrations reach 150 Ìg/l, whereas loss of consciousness with subsequent amnesia occurs at a dose of 3 mg/kg or an infusion rate of 1 mg/kg/h [30]. In general, an intravenous dose of 2 mg/kg ketamine in clinical use was reported to cause a peak plasma concentration of about 60 ÌM [30].…”

“…Analgesia occurs when concentrations reach 150 Ìg/l, whereas loss of consciousness with subsequent amnesia occurs at a dose of 3 mg/kg or an infusion rate of 1 mg/kg/h [30]. In general, an intravenous dose of 2 mg/kg ketamine in clinical use was reported to cause a peak plasma concentration of about 60 ÌM [30]. In this study, we chose the concentration of collagen to be 1 Ìg/ml to trigger platelet aggregation.…”