http://michiganbraincoretherapy.com/storage/Scientific%20Research%20SOUTAR/KnyazevDelta.pdf

EEG delta oscillations as a correlate of basic homeostatic and motivational processes.

Fentanyl, a synthetic opiate with a (clinical) potency of 50 to 100 times that of morphine, was introduced into clinical practice in the early 1960s. Usually administered by single intravenous doses, it developed a reputation for having a short duration of action and it was assumed that this was a consequence of rapid removal from the body. However, as clinical experience increased, it was realised that administration of multiple doses or large doses during narcotic-based anaesthesia sometimes led to delayed recovery and prolonged respiratory depression, suggesting that the duration of action was limited by redistribution within the body rather than removal from the body. Recent developments in analytical techniques have allowed pharmacokinetic studies and these have confirmed this opinion; fentanyl is rightly regarded as having a redistribution-limited duration of action after single or infrequent doses (analogous to thiopentone). However, the magnitude of the pharmacokinetic constants reported for fentanyl are remarkably inconsistent even in healthy volunteers, for reasons apparently only explainable by assay differences. Hence, estimates of apparent volume of distribution (area) range from around 60L to over 300L, estimates of terminal half-life range from about 1.5 to 6 hours (15 hours in geriatric patients) and total body clearance ranges from 0.4 to over 1.5 L/min. Renal excretion accounts for up to 10% of the dose; the remainder of the clearance would appear to be predominantly hepatic, but with contributions from other tissues. Continued clinical developments of narcotic-based anaesthetic techniques have resulted in high doses of narcotic being used, with oxygen, as the sole anaesthetic agents. At present these techniques are usually based on fentanyl, and the technique is frequently called ’stressfree anaesthesia’ because of the effects in obtunding the ’stress response’ caused by surgery (elevation of plasma concentrations of cortisol, glucose, ADH, etc. in the intra- and postoperative period) and the lack of deleterious effects on the cardiovascular system. With the hypothesis that increased potency is associated with increased specific opiate effects and decreased nonspecific cardiovascular depressant effects, chemical congeners of fentanyl were developed. Alfentanil has about one-third the (clinical) potency of fentanyl, while sufentanil has about 5 to 10 times the (clinical) potency of fentanyl. Lofentanil and carfentanil have about 20 to 30 times the potency of fentanyl and have yet to find clinical roles. Alfentanil is characterised by a rather small apparent volume of distribution for a base (Varea = 40-70L), short terminal half-life (100 minutes), intermediate total body clearance (0.3–0.5 L/min) and negligible renal clearance. Sufentanil would appear to have pharmacokinetic properties intermediate to those of alfentanil and fentanyl. At physiological pH, approximately 15 to 20% of fentanyl is unbound in plasma compared with 5 to 10% of alfentanil, sufentanil and lofentanil. Except for alfentanil, there is a marked plasma binding dependence on pH. Also except for alfentanil, there is a predominance of ionised drug species and a high octanol: water partition coefficient in the physiological pH range. These factors act to influence the tissue binding of the agents and reflect back on other important factors such as uptake by blood cells. Whole blood: plasma concentration ratios of 0.97, 0.63, 0.74 and 0.71 have been reported for fentanyl, alfentanil, sufentanil and lofentanil, respectively. The range of opiate duration of action has been extended by the appearance of these newer compounds, where alfentanil may be regarded as having an ultrashort duration of action, fentanyl and sufentanil as short acting, while lofentanil has a long duration of action. Knowledge of the pharmacokinetic properties of these agents has provided more information than could be obtained from clinical studies alone, and has added a basis on which to rationalise and enhance their usefulness.

Clinical Pharmacokinetics of Fentanyl and its Newer Derivatives

Objectives Therapeutic hypothermia has been shown to decrease neurologic damage in patients experiencing out-of-hospital cardiac arrest. In addition to being treated with hypothermia, critically ill patients are treated with an extensive pharmacotherapeutic regimen. The effects of hypothermia on drug disposition increase the probability for unanticipated toxicity, which could limit its putative benefit. This review examines the effects of therapeutic hypothermia on the disposition, metabolism, and response of drugs commonly used in the intensive care unit, with a focus on the cytochrome P450 enzyme system. Data sources and study selection A MEDLINE/PubMed search from 1965 to June 2006 was conducted using the search terms hypothermia, drug metabolism, P450, critical care, cardiac arrest, traumatic brain injury, and pharmacokinetics. Data extraction and synthesis Twenty-one studies were included in this review. The effects of therapeutic hypothermia on drug disposition include both the effects during cooling and the effects after rewarming on drug metabolism and response. The studies cited in this review demonstrate that the addition of mild to moderate hypothermia decreases the systemic clearance of cytochrome P450 metabolized drugs between approximately 7% and 22% per degree Celsius below 37degreesC during cooling. The addition of hypothermia decreases the potency and efficacy of certain drugs. Conclusions This review provides evidence that the therapeutic index of drugs is narrowed during hypothermia. The magnitude of these alterations indicates that intensivists must be aware of these alterations in order to maximize the therapeutic efficacy of this modality. In addition to increased clinical attention, future research efforts are essential to delineate precise dosing guidelines and mechanisms of the effect of hypothermia on drug disposition and response.

Effects of hypothermia on drug disposition, metabolism, and response: A focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system.

Protein-losing enteropathy after the Fontan operation.

The synthetic opioid fentanyl undergoes extensive metabolism in humans. Systemic elimination occurs primarily by hepatic metabolism. When administered as a lozenge for oral transmucosal absorption, swallowed fentanyl is subject to first pass metabolism in the liver and possibly small intestine. Little is known, however, about the identity and formation of human fentanyl metabolites. This investigation identified routes of human liver microsomal fentanyl metabolism and their relative importance, tested the hypothesis that fentanyl is metabolized by human duodenal microsomes, and identified the predominantly responsible cytochrome P450 isoforms. A GC/MS assay using deuterated internal standards was developed for fentanyl metabolites. Piperidine N-dealkylation to norfentanyl was the predominant pathway of liver microsomal metabolism. Amide hydrolysis to despropionylfentanyl and alkyl hydroxylation to hydroxyfentanyl were comparatively minor pathways. Hydroxynorfentanyl was identified as a minor, secondary metabolite arising from N-dealkylation of hydroxyfentanyl. Liver microsomal norfentanyl formation was significantly inhibited by the mechanism-based P450 3A4 inhibitor troleandomycin and the P450 3A4 substrate and competitive inhibitor midazolam, and was significantly correlated with P450 3A4 protein content and catalytic activity. Of six expressed human P450 isoforms (P450s 1A2, 2B6, 2C9, 2D6, 2E1, and 3A4), only P450 3A4 exhibited significant fentanyl dealkylation to norfentanyl. These results indicate the predominant role of P450 3A4 in the primary route of hepatic fentanyl metabolism. Human duodenal microsomes also catalyzed fentanyl metabolism to norfentanyl; the average rate was approximately half that of hepatic metabolism. Rates of duodenal norfentanyl formation were diminished by troleandomycin and midazolam, and were significantly correlated with P450 3A4 activity, suggesting a prominent role for P450 3A4. These results demonstrate that human intestinal as well as liver microsomes catalyze fentanyl metabolism, and N-dealkylation by P450 3A4 is the predominant route in both organs. The fraction of fentanyl lozenge that is swallowed likely undergoes significant intestinal, as well as hepatic, first-pass metabolism. Intestinal and hepatic first-pass metabolism, as well as systemic metabolism, may be subject to individual variability in P450 3A4 expression and to drug interactions involving P450 3A4.

Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions.

The pharmacokinetics of sufentanil, a new thienyl analogue of fentanyl, were studied in 10 surgical patients. Sufentanil, 5 micrograms/kg, was given intravenously as a bolus injection and plasma concentrations measured at intervals up to 8 h. Plasma sufentanil concentrations decreased rapidly after injection--98% of the administered dose having left the plasma within 30 min. In 9 of the 10 patients, a tri-exponential equation optimally described the sufentanil concentration decay curve, with average (+/-SEM) half-lives for the rapid (pi) and slow (alpha) distribution phases of 1.4 +/- 0.3 min and 17.7 +/- 2.6 min, respectively. The average terminal elimination (beta) half-life was 164 +/- 22 min. The average value for Vd beta was 2.9 +/- 0.2 1/kg, Vdss 1.7 +/- 0.2 1/kg and total plasma clearance 12.7 +/- 0.8 ml X kg-1 X min-1 (935 +/- 50 ml/min). In one patient, a bi-exponential equation was sufficient to describe the concentration-time data, yielding a distribution half-life of 4.7 min and an elimination half-life of 117 min.

The Pharmacokinetics of Sufentanil in Surgical Patients

SUMMARY The pharmacokinetics following a bolus injection of fentanyl 60 μg kg−1 as the sole anaesthetic in five patients undergoing cardiac surgery are described. Before cardiopulmonary bypass the kinetics can be described by a biexponenrial decay curve with an initial half-life of 1.7±0.85 min and a half-life during the tissue uptake phase of 69±8.2 min. Two patients had secondary peaks in plasma fentanyl concentration during the first 5 min after injection. After 5 min cardiopulmonary bypass with haemodilution, the fentanyl concentration decreased by an average of 53%. The half-life in the post-bypass elimination phase was 423±36.9 min. No second peaks during the elimination phase were found.

Pharmacokinetics of high-dose fentanyl. A study in patients undergoing cardiac surgery.

Fontan's operation: an expanded horizon.

SUMMARY The effects of anaesthesia with sufentanil 15 μg kg−1, air and oxygen on the electroencephalograph were studied in 12 patients before and after cardiopulmonary bypass. The e.e.g. responses were characterized by high voltage, slow delta waves. Although the mean power in the delta band declined with time, the contribution of delta power to total power in the frequency range 0.5–40 Hz remained constant until the onset of cardiopulmonary bypass. Sharp waves of uncertain neurophysiological significance were seen. They were not associated with clinical signs of epileptic activity. The use of the e.e.g. response as a monitor of "depth of anaesthesia" during high-dose opioid anaesthesia may become possible.

Electroencephalographic effects of sufentanil anaesthesia in man

The influence of high-dose alfentanil-oxygen-air anaesthesia on the electroencephalogram was studied in 10 patients undergoing elective coronary artery surgery. Premedication was either lorazepam 5 mg orally (n = 5) or morphine 10 mg and hyoscine 0.4 mg i.m. (n = 5). Anaesthesia was induced with alfentanil 125 micrograms kg-1 h-1 and maintained by a continuous infusion at a rate of 0.25-0.5 mg kg-1. The EEG was recorded on the day before surgery, continuously from before induction of anaesthesia until the end of surgery and at hourly intervals after operation. Blood samples were withdrawn at intervals during and after surgery for measurement of plasma alfentanil concentrations. Anaesthesia was associated with large increases in delta activity and reduction in higher frequency components. There was less synchronization of the EEG than is observed with fentanyl or sufentanil. Spindle activity was prominent in 70% of patients. The changes in the EEG during recovery tended to occur abruptly and there was no obvious correlation between the EEG and plasma concentrations of alfentanil. There was a significant correlation between the total dose of alfentanil and the awake plasma concentration (r = 0.94; P less than 0.01). Plasma concentrations decreased exponentially after operation, with a mean half-life of 304 +/- 54 min.

P.S. Sebel

Papers

The Pharmacokinetics of Sufentanil in Surgical Patients

Pharmacokinetics of high-dose fentanyl. A study in patients undergoing cardiac surgery.

Fontan's operation: an expanded horizon.

Electroencephalographic effects of sufentanil anaesthesia in man

Influence of high-dose alfentanil anaesthesia on the electroencephalogram: correlation with plasma concentrations.