David R. Drover

Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: Zaleplon, Zolpidem and Zopiclone

Benzodiazepines have historically been the mainstay of treatment for sleeping disorders, yet they have many shortcomings. A new group of sedative hypnotic agents has been developed for this purpose. Similar to the benzodiazepines, zaleplon, zolpidem and zopiclone have activity at the GABA receptor complex, yet they appear to have more selectivity for certain subunits of the GABA receptor. This produces a clinical profile that is more efficacious with fewer side effects. Zaleplon, zolpidem and zopiclone are structurally distinct. Due to variation in binding to the GABA receptor subunits, these three compounds show subtle differences in their effect on sleep stages, and as antiepileptics, anxiolytics and amnestics.The duration of action of zaleplon, zolpidem and zopiclone can be related to their individual pharmacokinetic profile, which subsequently determines the time course of drug effect. Each of these compounds has a unique pharmacokinetic profile with different bioavailability, volume of distribution and elimination half-lives. Zaleplon has a rapid elimination so there are fewer residual side effects after taking a single dose at bedtime. By comparison, zolpidem and zopiclone have a more delayed elimination so there may be a prolonged drug effect. This can result in residual sedation and side effects but may be useful for sustained treatment of insomnia with less waking during the night. There are also differences in potency based on plasma concentrations suggesting that there are differences in binding to the GABA receptor complex. Although zaleplon has a much lower bioavailability (30%), the treatment dose is similar to zolpidem and zopiclone (bioavilaibility of 70%) because of the increased potency of zaleplon.The pharmacokinetics and pharmacodynamics of zaleplon, zolpidem and zopiclone are significantly different from benzodiazepines. The new drugs are sufficiently unique from each other to allow customisation of treatment for various types of insomnia. While zaleplon may be best indicated for the delayed onset of sleep, zolpidem and zopiclone may be better indicated for maintaining a complete night’s sleep. Only the patient’s symptoms and response to treatment will dictate the best course of treatment.

The effects of dexmedetomidine on cardiac electrophysiology in children.

BACKGROUND:Dexmedetomidine (DEX) is an &agr;2-adrenergic agonist that is approved by the Food and Drug Administration for short-term (<24 h) sedation in adults. It is not approved for use in children. Nevertheless, the use of DEX for sedation and anesthesia in infants and children appears to be increasing. There are some concerns regarding the hemodynamic effects of the drug, including bradycardia, hypertension, and hypotension. No data regarding the effects of DEX on the cardiac conduction system are available. We therefore aimed to characterize the effects of DEX on cardiac conduction in pediatric patients. METHODS:Twelve children between the ages of 5 and 17 yr undergoing electrophysiology study and ablation of supraventricular accessory pathways had hemodynamic and cardiac electrophysiologic variables measured before and during administration of DEX (1 &mgr;g/kg IV over 10 min followed by a 10-min continuous infusion of 0.7 &mgr;g · kg−1 · h−1). RESULTS:Heart rate decreased while arterial blood pressure increased significantly after DEX administration. Sinus node function was significantly affected, as evidenced by an increase in sinus cycle length and sinus node recovery time. Atrioventricular nodal function was also depressed, as evidenced by Wenckeback cycle length prolongation and prolongation of PR interval. CONCLUSION:DEX significantly depressed sinus and atrioventricular nodal function in pediatric patients. Heart rate decreased and arterial blood pressure increased during administration of DEX. The use of DEX may not be desirable during electrophysiology study and may be associated with adverse effects in patients at risk for bradycardia or atrioventricular nodal block.

A Randomized, Dose-Finding, Phase II Study of the Selective Relaxant Binding Drug, Sugammadex, Capable of Safely Reversing Profound Rocuronium-Induced Neuromuscular Block

BACKGROUND:The reversal of a deep neuromuscular blockade remains a significant clinical problem. Sugammadex, a modified &ggr;-cyclodextrin, encapsulates steroidal neuromuscular blocking drugs, promoting their rapid dissociation from nicotinic receptors. Sugammadex is the first drug that acts as a selective relaxant binding agent. METHODS:We enrolled 50 patients into a Phase II dose-finding study of the efficacy and safety of sugammadex. Subjects, anesthetized with nitrous oxide and propofol, were randomized to one of two doses of rocuronium (0.6 or 1.2 mg/kg) and to one of five doses of sugammadex (0.5, 1.0, 2.0, 4.0, or 8.0 mg/kg). Neuromuscular monitoring was performed using the TOF Watch SX® acceleromyograph. Recovery was defined as a train-of-four ratio ≥0.9. Sugammadex was administered during profound block when neuromuscular monitoring demonstrated a posttetanic count of one or two. RESULTS:Reversal of neuromuscular block was obtained after administration of sugammadex in all but the lowest dose groups (0.5–1.0 mg/kg) where several subjects could not be adequately reversed. At the 2 mg/kg dose all patients were reversed with sugammadex, but there was significant variability (1.8–15.2 min). Patient variability decreased and speed of recovery increased in a dose-dependent manner. At the highest dose (8 mg/kg), mean recovery time was 1.2 min (range 0.8–2.1 min). No serious adverse events were reported during this trial. CONCLUSIONS:Sugammadex was well tolerated and effective in rapidly reversing profound rocuronium-induced neuromuscular block. The mean time to recovery decreased with increasing doses. Profound rocuronium-induced neuromuscular block can be reversed successfully with sugammadex at doses ≥2 mg/kg.

Patient state index : titration of delivery and recovery from propofol, alfentanil, and nitrous oxide anesthesia

Background The Patient State Index (PSI) uses derived quantitative electroencephalogram features in a multivariate algorithm that varies as a function of hypnotic state. Data are recorded from two anterior, one midline central, and one midline posterior scalp locations. PSI has been demonstrated to have a significant relation to level of hypnosis during intravenous propofol, inhalation, and nitrous oxide–narcotic anesthesia. This multisite study evaluated the utility of PSI monitoring as an adjunct to standard anesthetic practice for guiding the delivery of propofol and alfentanil to accelerate emergence from anesthesia. Methods Three hundred six patients were enrolled in this multicenter prospective randomized clinical study. Using continuous monitoring throughout the period of propofol–alfentanil–nitrous oxide anesthesia delivery, PSI guidance was compared with use of standard practice guidelines (both before [historic controls] and after exposure to the PSA 4000 monitor [Physiometrix, Inc., N. Billerica, MA; standard practice controls]). Anesthesia was always administered with the aim of providing hemodynamic stability, with rapid recovery. Results No significant differences were found for demographic variables or for site. The PSI group received significantly less propofol than the standard practice control group (11.9 &mgr;g · kg−1 · min−1;P < 0.01) and historic control group (18.2 &mgr;g · kg−1 · min−1;P < 0.001). Verbal response time, emergence time, extubation time, and eligibility for operating room discharge time were all significantly shorter for the PSI group compared with the historic control (3.3–3.8 min;P < 0.001) and standard practice control (1.4–1.5 min;P < 0.05 or P < 0.01) groups. No significant differences in the number of unwanted somatic events or hemodynamic instability and no incidences of reported awareness were found. Conclusions Patient State Index–directed titration of propofol delivery resulted in faster emergence and recovery from propofol–alfentanil–nitrous oxide anesthesia, with modest decrease in the amount of propofol delivered, without increasing the number of unwanted events.

ED50 and ED95 of intrathecal hyperbaric bupivacaine coadministered with opioids for cesarean delivery

BackgroundSuccessful cesarean delivery anesthesia has been reported with use of small doses (5–9 mg) of intrathecal bupivacaine coadministered with opioids. This double-blind, randomized, dose-ranging study determined the ED50 and ED95 of intrathecal bupivacaine (with adjuvant opioids) for cesarean delivery anesthesia. MethodsForty-two parturients undergoing elective cesarean delivery with use of combined spinal–epidural anesthesia received intrathecal hyperbaric bupivacaine in doses of 6, 7, 8, 9, 10, 11, or 12 mg in equal volumes with an added 10 &mgr;g intrathecal fentanyl and 200 &mgr;g intrathecal morphine. Sensory levels (pinprick) were evaluated every 2 min until a T6 level was achieved. The dose was a success(induction) if a bilateral T6 block occurred in 10 min; otherwise, it was a failure(induction). In addition to being a success(induction), the dose was a success(operation) if no intraoperative epidural supplement was required; otherwise, it was a failure(operation). ED50 and ED95 for both success(induction) and success(operation) were determined with use of a logistic regression model. ResultsED50 for success(induction) and success(operation) were 6.7 and 7.6 mg, respectively, whereas the ED95 for success(induction) and success(operation) were 11.0 and 11.2 mg. Speed of onset correlated inversely with dose. Although no clear advantage for low doses could be demonstrated (hypotension, nausea, vomiting, pruritus, or maternal satisfaction), this study was underpowered to detect significance in these variables. ConclusionsThe ED95 of intrathecal bupivacaine under the conditions of this study is considerably in excess of the low doses proposed for cesarean delivery in some recent publications. When doses of intrathecal bupivacaine less than the ED95, particularly near the ED50, are used, the doses should be administered as part of a catheter-based technique.

Pharmacodynamics of orally administered sustained- release hydromorphone in humans.

BackgroundThe disposition kinetics of hydromorphone generally necessitates oral administration every 4 h of the conventional immediate-release tablet to provide sustained pain relief. This trial examined time course and magnitude of analgesia to experimental pain after administration of sustained-release hydromorphone as compared with that after immediate-release hydromorphone or placebo. MethodsUsing a 4 × 4 Latin square double-blind design, 12 subjects were randomized to receive a single dose of 8, 16, and 32 mg sustained-release hydromorphone and placebo. The same subjects had received 8 mg immediate-release hydromorphone before this study. Using an electrical experimental pain paradigm, analgesic effects were assessed for up to 30 h after administration, and venous hydromorphone plasma concentrations were measured at corresponding times. ResultsThe hydromorphone plasma concentration peaked significantly later (12.0 h [12.0–18.0]vs. 0.8 h [0.8–1.0]; median and interquartile range) but was maintained significantly longer at greater than 50% of peak concentration (22.7 ± 8.2 h vs. 1.1 ± 0.7 h; mean ± SD) after sustained-release than after immediate-release hydromorphone. Similarly, sustained-release hydromorphone produced analgesic effects that peaked significantly later (9.0 h [9.0–12.0]vs. 1.5 h [1.0–2.0]) but were maintained significantly longer at greater than 50% of peak analgesic effect (13.3 ± 6.3 h vs. 3.6 ± 1.7 h). A statistically significant linear relation between the hydromorphone plasma concentration and the analgesic effect on painful stimuli existed. ConclusionA single oral dose of a new sustained-release formulation of hydromorphone provided analgesia to experimental pain beyond 24 h of its administration.

Input Characteristics and Bioavailability after Administration of Immediate and a New Extended-release Formulation of Hydromorphone in Healthy Volunteers

Background To compare the pharmacokinetics of intravenous, oral immediate-release (IR), and oral extended-release (OROS®) formulations of hydromorphone. Methods In this randomized, six-session, crossover-design study, 12 subjects received hydromorphone 8-mg intravenous, 8-mg IR oral, and 8-, 16-, and 32-mg OROS® formulations or placebo orally followed by plasma sampling for hydromorphone determination. Pharmacokinetic analysis was performed using NONMEM. Using the disposition of hydromorphone from the intravenous administration, deconvolution was used to estimate the input rate function (release rate from the gut to the blood) for the IR and OROS® formulations. A linear spline was used to describe the drug input rate function. Results The deconvolution using linear splines described the in vivo release characteristics of both the IR and OROS® formulations. The mean absolute bioavailability for the 8-mg OROS® formulation was significantly larger (P = 0.025) than for the 8-mg IR formulation: 0.24 (SD 0.059) versus 0.19 (SD 0.054), respectively. The bioavailability was the same for the three doses of the OROS® formulation. Predicted degree of fluctuation of plasma concentrations would be expected to be 130% and 39% for the IR and OROS® 8-mg doses, respectively. Conclusions The OROS® formulation of hydromorphone produced continued release of medication over 24 h, which should allow for once-daily oral dosing. The extended release of hydromorphone will produce less fluctuation of plasma concentrations compared with IR formulations, which should provide for more constant pain control. The in vivo release of hydromorphone from both IR and OROS® formulations were adequately described using a linear spline deconvolution approach. The increased bioavailability from the OROS® formulation may be related to decreased metabolism by a first-pass effect or enterohepatic recycling of hydromorphone.

Pharmacology of drugs formulated with DepoFoam: a sustained release drug delivery system for parenteral administration using multivesicular liposome technology.

Lamellar liposome technology has been used for several decades to produce sustained-release drug formulations for parenteral administration. Multivesicular liposomes are structurally distinct from lamellar liposomes and consist of an aggregation of hundreds of water-filled polyhedral compartments separated by bi-layered lipid septa. The unique architecture of multivesicular liposomes allows encapsulating drug with greater efficiency, provides robust structural stability and ensures reliable, steady and prolonged drug release.The favourable characteristics of multivesicular liposomes have resulted in many drug formulations exploiting this technology, which is proprietary and referred to as DepoFoam™. Currently, two formulations using multivesicular liposome technology are approved by the US FDA for clinical use, and many more formulations are at an experimental developmental stage. The first clinically available formulation contains the antineoplastic agent cytarabine (DepoCyt™) for its intrathecal injection in the treatment of malignant lymphomatous meningitis. Intrathecal injection of DepoCyt™ reliably results in the sustained release of cytarabine and produces cytotoxic concentrations in cerebrospinal fluid (CSF) that are maintained for at least 2 weeks. Early efficacy data suggest that DepoCyt™ is fairly well tolerated, and its use allows reduced dosing frequency from twice a week to once every other week and may improve the outcome compared with frequent intrathecal injections of unencapsulated cytarabine. The second available formulation contains morphine (DepoDur™) for its single epidural injection in the treatment of postoperative pain. While animal studies confirm that epidural injection of DepoDur™ results in the sustained release of morphine into CSF, the CSF pharmacokinetics have not been determined in humans. Clinical studies suggest that the use of DepoDur™ decreases the amount of systemically administered analgesics needed for adequate postoperative pain control. It may also provide superior pain control during the first 1–2 postoperative days compared with epidural administration of unencapsulated morphine or intravenous administration of an opioid. However, at this timepoint the overall clinical utility of DepoDur™ has yet to be defined and some safety concerns remain because of the unknown CSF pharmacokinetics of DepoDur™ in humans.The versatility of multivesicular liposome technology is reflected by the many agents including small inorganic and organic molecules and macromolecules including proteins that have successfully been encapsulated. Data concerning many experimental formulations containing antineoplastic, antibacterial and antiviral agents underscore the sustained, steady and reliable release of these compounds from multivesicular liposomes after injection by the intrathecal, subcutaneous, intramuscular, intraperitoneal and intraocular routes. Contingent on the specific formulation and manufacturing process, agents were released over a period of hours to weeks as reflected by a 2- to 400-fold increase in elimination half life. Published data further suggest that the encapsulation process preserves bioactivity of agents as delicate as proteins and supports the view that examined multivesicular liposomes were non-toxic at studied doses. The task ahead will be to examine whether the beneficial structural and pharmacokinetic properties of multivesicular liposome formulations will translate into improved clinical outcomes, either because of decreased drug toxicity or increased drug efficacy.

Pain sensitivity and opioid analgesia: a pharmacogenomic twin study.

TOC Summary This twin study demonstrates significant genetic and familial effects for pain sensitivity and opioid analgesia and provides a strong rationale for more detailed genetic studies. ABSTRACT Opioids are the cornerstone medication for the management of moderate to severe pain. Unfortunately, vast inter‐individual differences in dose requirements complicate their effective and safe clinical use. Mechanisms underlying such differences are incompletely understood, are likely multifactorial, and include genetic and environmental contributions. While accumulating evidence suggests that variants of several genes account for some of the observed response variance, the relative contribution of these factors remains unknown. This study used a twin paradigm to provide a global estimate of the genetic and environmental contributions to inter‐individual differences in pain sensitivity and analgesic opioid effects. Eighty one monozygotic and 31 dizygotic twin pairs successfully underwent a computer‐controlled infusion with the μ‐opioid agonist alfentanil in a single occasion, randomized, double‐blind and placebo‐controlled study design. Pain sensitivity and analgesic effects were assessed with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. Significant heritability was detected for cold pressor pain tolerance and opioid‐mediated elevations in heat and cold pressor pain thresholds. Genetic effects accounted for 12–60% of the observed response variance. Significant familial effects accounting for 24–32% of observed variance were detected for heat and cold pressor pain thresholds and opioid‐mediated elevation in cold pressor pain tolerance. Significant covariates included age, gender, race, education, and anxiety. Results provide a strong rationale for more detailed molecular genetic studies to elucidate mechanisms underlying inter‐individual differences in pain sensitivity and analgesic opioid responses. Such studies will require careful consideration of the studied pain phenotype.

Efficacy, Safety, and Pharmacokinetics of Sugammadex for the Reversal of Rocuronium-induced Neuromuscular Blockade in Elderly Patients

Background:The management of elderly patients can be challenging for anesthesiologists for many reasons, including altered pharmacokinetics and dynamics. This study compared the efficacy, safety, and pharmacokinetics of sugammadex for moderate rocuronium-induced neuromuscular blockade reversal in adult (aged 18–64 yr) versus elderly adult (aged 65 yr or older) patients. Methods:This phase 3a, multicenter, parallel-group, comparative, open-label study enrolled 162 patients aged 18 yr and older, American Society of Anesthesiologists class 1–3, scheduled for surgery with general anesthesia and requiring neuromuscular blockade. After anesthesia induction, patients received rocuronium, 0.6 mg/kg, before tracheal intubation, with maintenance doses of 0.15 mg/kg as required. At the end of surgery, patients received sugammadex, 2.0 mg/kg, at reappearance of the second twitch of the train-of-four (TOF) for reversal. The primary efficacy variable was time from sugammadex administration to recovery of the TOF ratio to 0.9 or greater. Pharmacokinetics and safety were also evaluated. Results:Overall, 150 patients were treated and had at least one postbaseline efficacy assessment; 48 were aged 18–64 yr (adult), 62 were aged 65–74 yr (elderly), and 40 were aged 75 yr or older (old-elderly). The geometric mean time (95% confidence interval) from sugammadex administration to recovery of the TOF ratio to 0.9 increased with age, from 2.3 (2.0–2.6) min (adults) to 2.9 (2.7–3.2) min (elderly/old-elderly groups combined). Recovery of the TOF ratio to 0.9 was estimated to be 0.7 min faster in adults compared with patients aged 65 yr or older (P = 0.022). Sugammadex was well tolerated by all patients. Conclusion:Sugammadex facilitates rapid reversal from moderate rocuronium-induced neuromuscular blockade in adults of all ages.