Pharmacodynamics Of Dexmedetomidine Research Articles

Management of severe delirium with dexmedetomidine in a palliative care patient—a case report

Dexmedetomidine is used as an adjunct to anaesthesia or as a stand-alone agent for conscious sedation. It is a potent α2-adrenergic receptor agonist, with a fast onset of action and peak effects in 30 minutes to 1 hour after application, depending on the route of administration. It is metabolized in the liver and excreted in urine as a glucuronide. It potentiates analgesia and is effective in opioid sparing. Clinical trials show its efficacy in the treatment of Intensive Care Unit (ICU) delirium with an effect comparable to antipsychotics and benzodiazepines. It has also been used at the Eye Clinic of the University Medical Centre Ljubljana to sedate patients undergoing intraocular surgery. It proved to be an excellent alternative to other sedatives and analgesics, such as midazolam and remifentanil. The aim of this paper is to review the pharmacokinetics and pharmacodynamics of dexmedetomidine and to investigate its potential use in the palliative care population, particularly in the management of delirium. This area of application is still largely unexplored and opens up a new field of application. At the Institute of Oncology (IO) Ljubljana, we have used it with success in several palliative patients with delirium, when all other modalities were failing. At the IO Ljubljana, anaesthesiologists are involved in the palliative management of patients, especially in pain management, but also in sedation and delirium treatment. Given its favourable pharmacokinetic and pharmacodynamic effects, dexmedetomidine could be used more frequently and perhaps alternative and less complex routes of administration, such as intranasal administration, could be explored. In this paper, we present a case of a palliative care patient in whom dexmedetomidine was used successfully.

Pharmacokinetics and pharmacodynamics of intramuscular dexmedetomidine in dogs.

To determine the pharmacokinetics and pharmacodynamics of dexmedetomidine after IM administration in dogs. 6 healthy adult purpose-bred dogs (3 males, 3 females) with a mean ± SD body weight of 25.2 ± 1.8 kg. Each dog received 10 µg/kg dexmedetomidine, IM. Heart rate and respiratory rate were counted via cardiac auscultation and visual assessment of chest excursions. Sedation was assessed utilizing 2 sedation scoring systems. Plasma concentrations were determined using ultra performance liquid chromatography-mass spectrometry. Plasma concentrations versus time data after IM dexmedetomidine were analyzed using noncompartmental analysis for extravascular administration. Over the first 2 hours following IM injection of dexmedetomidine, plasma concentrations fluctuated in each dog. The geometric mean (range) maximum plasma concentration was 109.2 (22.4 to 211.5) ng/mL occurring at 20.5 (5 to 75) minutes, and the mean half-life was 25.5 (11.5 to 41.5) minutes. Heart rate was significantly lower than baseline from 30 minutes to 2 hours postdexmedetomidine administration, and respiratory rate was significantly lower than baseline from 45 minutes to 1.75 hours. Dogs were significantly more sedated from 30 minutes to 1.5 hours postdexmedetomidine administration. Median time to onset of sedation was 7.5 minutes (range, 2 to 10 minutes), and median time to peak sedation was 30 minutes (range, 15 to 60 minutes). Variations in plasma concentrations occurred in all dogs for the 2 hours postinjection of dexmedetomidine at 10 µg/kg, IM. This was likely due to alterations in absorption due to dexmedetomidine-induced local vasoconstriction. Despite variable plasma concentrations, all dogs were sedated following IM dexmedetomidine administration.

Perioperative Low Dose Dexmedetomidine and Its Effect on the Visibility of the Surgical Field for Middle Ear Microsurgery: A Randomised Controlled Trial.

Background and Purpose: There are many benefits of administering dexmedetomidine perioperatively. The pharmacokinetics (PK) and pharmacodynamics (PD) of intravenous, intranasal and oral dexmedetomidine that was administered before anesthesia were compared in this study, and the effects of dexmedetomidine on the surgical field visibility in tympanoplasty was evaluated. Methods: A single-blind, randomized controlled trial was conducted in a university-affiliated hospital where 45 patients who underwent tympanoplasty under general anesthesia were randomly allocated into three groups. Dexmedetomidine was administered by intravenous infusion at 0.8 μg.kg−1 for 10 min, intranasal instillation at a drop rate of 1 μg.kg−1 and oral intake at 4 μg.kg−1 ten minutes before the induction of anesthesia. The PK and PD of dexmedetomidine after a single low dose administration and its effect on the surgical field in tympanoplasty were analysed. Results: A plasma concentration of dexmedetomidine of 220 pg/ml was achieved immediately after intravenous infusion and at 13.2 and 70.3 min for intranasal and oral administration, respectively. Dexmedetomidine decreased the heart rate (HR) and mean arterial pressure (MAP) in all three groups, although these values remained higher in the oral dexmedetomidine group at all eight time points. Intravenous dexmedetomidine provided the best visualization of the surgical field for opening of the tympanic sinus, 30 min after the start of the infusion (p < 0.05). Intranasal dexmedetomidine provided a significantly better visual field than oral dexmedetomidine for the repair of a tympanic membrane perforation using the fascia temporal muscle (p < 0.05). Conclusion: A single low dose of dexmedetomidine administered intravenously or intranasally could decrease HR and MAP, improve surgical field visibility and be appropriate for deliberate hypotension for surgical procedures of 1–2 h in length. Trial registration: Clinicaltrials.gov identifier: NCT03800641.

Population analysis to assess the influence of age and body weight on pharmacokinetics and pharmacodynamics of dexmedetomidine in New Zealand White rabbits.

The purpose of this work was i) to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model of dexmedetomidine (DEX) in New Zealand White rabbits, ii) to investigate the influence of the age and weight of the animals on the model parameters, and iii) to assess the linearity of DEX PKs in the examined dose range. This was a prospective, crossover study, using a total of 18 New Zealand White rabbits. DEX was administered as a single intravenous bolus injection in the doses from 25 to 300 μg kg-1 . Each New Zealand White rabbit was given the same dose of drug in its three developmental stages. To determine the DEX PK, seven blood samples were taken from each animal. The pedal withdrawal reflex was the PD response used to assess the degree of sedation. Nonlinear mixed effects modelling was used for the population PK/PD analysis. The typical value of elimination clearance was 0.061 L min-1 and was 35% higher in younger New Zealand White rabbits compared with older animals. The PK of DEX was linear in the examined concentration range. Age-related changes in sensitivity to DEX were not detected. The results suggest that due to the pharmacokinetics, younger animals will have lower DEX concentrations and a shorter duration of sedation than older animals given the same doses of DEX per kg of body weight.

Population Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Children Undergoing Ambulatory Surgery.

BACKGROUND:Dexmedetomidine (DEX) is an α-2 adrenergic agonist with sedative and analgesic properties. Although not approved for pediatric use by the Food and Drug Administration, DEX is increasingly used in pediatric anesthesia and critical care. However, very limited information is available regarding the pharmacokinetics of DEX in children. The aim of this study was to investigate DEX pharmacokinetics and pharmacodynamics (PK–PD) in Mexican children 2–18 years of age who were undergoing outpatient surgical procedures.METHODS:Thirty children 2–18 years of age with American Society of Anesthesiologists physical status score of I/II were enrolled in this study. DEX (0.7 μg/kg) was administered as a single-dose intravenous infusion. Venous blood samples were collected, and plasma DEX concentrations were analyzed with a combination of high-performance liquid chromatography and electrospray ionization-tandem mass spectrometry. Population PK–PD models were constructed using the Monolix program.RESULTS:A 2-compartment model adequately described the concentration–time relationship. The parameters were standardized for a body weight of 70 kg by using an allometric model. Population parameters estimates were as follows: mean (between-subject variability): clearance (Cl) (L/h × 70 kg) = 20.8 (27%); central volume of distribution (V1) (L × 70 kg) = 21.9 (20%); peripheral volume of distribution (V2) (L × 70 kg) = 81.2 (21%); and intercompartmental clearance (Q) (L/h × 70 kg) = 75.8 (25%). The PK–PD model predicted a maximum mean arterial blood pressure reduction of 45% with an IC50 of 0.501 ng/ml, and a maximum heart rate reduction of 28.9% with an IC50 of 0.552 ng/ml.CONCLUSIONS:Our results suggest that in Mexican children 2–18 years of age with American Society of Anesthesiologists score of I/II, the DEX dose should be adjusted in accordance with lower DEX clearance.

Pharmacokinetic and pharmacodynamics of intravenous dexmedetomidine in morbidly obese patients undergoing laparoscopic surgery.

This study was designed to investigate the pharmacokinetics and pharmacodynamics of dexmedetomidine in morbidly obese patients undergoing laparoscopic surgery. Morbidly obese (body mass index ≥40kg/m2) and normal weight patients scheduled for elective laparoscopic surgery were included (n=8, each group). After baseline hemodynamic measurement, dexmedetomidine 1μg/kg was administered over 10min. General anesthesia was induced with propofol 1.5mg/kg and fentanyl 4μg/kg 20min after completion of dexmedetomidine infusion; the lungs were mechanically ventilated after tracheal intubation. The pharmacokinetics of dexmedetomidine was analyzed by a noncompartment model. Hemodynamic data and peripheral oxygen saturation (SpO2) were measured up to 30 min after starting dexmedetomidine infusion. Sedation level was measured with the Observer's Assessment of Alertness/Sedation (OAA/S) scale. Peak plasma concentration, area under the curve to infinity, elimination half-life, and apparent volume of distribution were significantly larger in morbidly obese than in normal weight patients (3.75±0.56 vs. 2.54±0.32µg/l, P<0.001; 2174±335 vs. 1594±251ngh/l, P<0.001; 225±55 vs. 158±53min, P=0.02; 310±63 vs. 164±41 l, P<0.001, respectively). Although clearance was also higher in obese patients than in normal body weight patients (58.6±10.7 vs. 44.9±9.0 l/h, P=0.02), it was lower in obese patients than in normal body weight patients after normalization to total body weight (0.47±0.07 vs. 0.64±0.09 l/h/kg, P<0.001). There were no differences in systolic or diastolic blood pressure or heart rate between the two groups within the 30min. Sedation level was deeper and SpO2 was lower in morbidly obese than in normal weight patients. More patients in the morbidly obese patient group experienced deeper sedation after the start of the dexmedetomidine infusion (P<0.05). The pharmacokinetics and pharmacodynamics of dexmedetomidine are significantly different in morbidly obese patients compared with normal weight patients. Level of sedation was significantly deeper, and oxygen saturation was significantly lower, in morbidly obese than in normal weight patients, probably resulting from higher plasma concentration after infusion of 1.0µg/kg. ClinicalTrials.gov (NCT01864187), https://register.clinicaltrials.gov/prs/app/action/LoginUser?ts=1&cx=-jg9qo4 .

Effects of mild hypoalbuminemia on the pharmacokinetics and pharmacodynamics of dexmedetomidine in patients after major abdominal or thoracic surgery

Study ObjectiveTo explore the effects of mild hypoalbuminemia on pharmacokinetics and pharmacodynamics of dexmedetomidine in patients after major abdominal or thoracic surgery. DesignA prospective cohort study. SettingUniversity-affiliated teaching hospital. PatientsThe study was performed in 30 consecutive patients undergoing major abdominal or thoracic surgery. They were aged 18 to 65 years and graded as American Society of Anesthesiologists physical status I and II. All patients were scheduled to require more than 6 hours of postoperative sedation and mechanical ventilation. Nine of the patients had low plasma albumin levels (<35 g/L but >24 g/L; male/female, 6/3) after the operation, who were assigned to hypoalbuminemia group, and the remainder with normoalbuminemia (>35 g/L; male/female, 15/6) were assigned to normoalbuminemia group. InterventionsAll patients were administered a loading dose of dexmedetomidine 1.0 μg/kg infused over 10 minutes after admitted into intensive care unit and a maintenance dose of 0.4 μg/kg per hour followed for 6 hours. MeasurementsPlasma dexmedetomidine levels were determined by high performance liquid chromatography – mass spectrum. Sedation was evaluated using Ramsay sedation score. Heart rate and arterial pressures were monitored. Adverse events were recorded. Main ResultsCompared with patients with normoalbuminemia, maximum plasma concentration of dexmedetomidine decreased by 21.2% in patients with hypoalbuminemia (P < .01). Its volume of distribution at steady state increased by 40.5%; elimination half-life decreased by 33.5% (P < .01). However, heart rates, arterial pressures, and Ramsay sedation scores did not differ significantly between the 2 groups. No serious adverse events occurred in either the patients with hypoalbuminemia or normoalbuminemia. ConclusionsSedation and adverse reactions of dexmedetomidine infusion did not differ significantly between patients with mild hypoalbuminemia and normoalbuminemia, although its volume of distribution at steady state increased and elimination half-life shortened in patients with hypoalbuminemia. This suggests that dexmedetomidine infusion can safely be used in mild hypoalbuminemia patients after major abdominal or thoracic surgery.

The influence of age and dosage on the pharmacodynamics of dexmedetomidine in rabbits

Aim. This study aimed to examine the influence of maturation and dosage on the sedative and haemodynamic response observed in rabbits after the administration of dexmedetomidine. Material and methods. The pharmacodynamics of dexmedetomidine was studied on 14 healthy New Zealand white rabbits at three periods of maturation; stage 1–1.5 months old, stage 2–2.5 months old and stage 3–6.5 months old ones. The administered dose of dexmedetomidine ranged from 25 µg/kg to 300 µg/kg of body weight. The pedal withdrawal reflex was used to measure the duration of anaesthesia. The heart rate and mean arterial pressure were measured at the third stage of the study to evaluate the haemodynamic response. A simple pharmacodynamic relationship between the dose and the duration of anesthesia was used to describe the data.Results. We observed that young rabbits were less sensitive to dexmedetomidine than adult animals, as was reflected by the pedal withdrawal reflex, and we found that the haemodynamic response to dexmedetomidine depended on dosage of the drug. Dexmedetomidine decreased the mean blood pressure in a dosage-dependent manner with the highest decrease observed for the lowest dose. As the dose increased, the hypotensive effect of the drug was less noticeable. After the administration of dexmedetomidine the heart rate decreased to the same value regardless of the dose applied.

Dexmedetomidin

Dexmedetomidine is a highly selective, potent α₂-adrenoceptor agonist which was approved in 2011 by the European Medicines Agency for sedation of patients in intensive care units (ICU). Dexmedetomidine exhibits sedative as well as analgesic and anxiolytic effects. Recent studies suggest that dexmedetomidine may be an alternative to midazolam in long-term ICU sedation. This review summarizes the pharmacokinetics and pharmacodynamics of dexmedetomidine particularly in ICU patients and with special regard to covariate effects. Although dexmedetomidine is currently approved only for use in adults the pharmacokinetics and pharmacodynamics in children will also be addressed as there are numerous studies on this off-label use.

Pharmacokinetics of dexmedetomidine in postsurgical pediatric intensive care unit patients: Preliminary study*

To characterize the pharmacokinetics of dexmedetomidine and monitor any dexmedetomidine-related adverse events in postoperative pediatric patients requiring short-term mechanical ventilation, analgesia, and sedation in the pediatric intensive care unit (PICU). Prospective, case series. Operating room and PICU in a large, urban children's hospital. Enrollment from February 14 to November 25, 2002. Ten children (4 months to 7.9 yrs of age) who received postoperative infusions of dexmedetomidine. Toward the end of the operation, patients received dexmedetomidine at 1 microg/kg per hr for 10 mins. The anesthesiologist then titrated the infusion, as clinically indicated, to a rate of 0.2-0.7 microg/kg per hr. In the PICU, the infusion was titrated by the nursing staff based on assessment with a modified Ramsey Sedation Scale, while maintaining heart rate and blood pressure within normal limits for age. Dexmedetomidine was continued until the intensivist felt the patient no longer benefited, but for no longer than 24 hrs. At specified times during the infusion and after discontinuation, dexmedetomidine plasma concentrations were determined. Pharmacokinetic parameters were calculated using a two-compartment model. Vital signs, sedation scores, adjunct sedative or analgesic medications, and adverse events were recorded. Average duration of infusion was 18.8 hrs (range, 8-24 hrs). Means (+/-sd) were calculated for the following: clearance, 0.57 (+/-0.14) L/hr per kg; volume of distribution at steady state, 1.53 (+/-0.37) L/kg; and terminal elimination half-life, 2.65 (+/-0.88 hrs)-all similar to published values in adults. There were no serious adverse events related to dexmedetomidine. Dexmedetomidine, administered as a continuous infusion, produces consistent, predictable concentrations in children and infants. Further evaluations of the safety, efficacy, and pharmacodynamics of dexmedetomidine are warranted.

A Phase I, Two-Center Study of the Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Children

A Phase I, Two-Center Study of the Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Children

A Phase I, Two-center Study of the Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Children

To investigate dexmedetomidine in children, the authors performed an open-label study of the pharmacokinetics and pharmacodynamics of dexmedetomidine. Thirty-six children were assigned to three groups; 24 received dexmedetomidine and 12 received no drug. Three doses of dexmedetomidine, 2, 4, and 6 microg x kg x h, were infused for 10 min. Cardiorespiratory responses and sedation were recorded for 24 h. Plasma concentrations of dexmedetomidine were collected for 24 h and analyzed. Pharmacokinetic variables were determined using nonlinear mixed effects modeling (NONMEM program). Cardiorespiratory responses were analyzed. Thirty-six children completed the study. There was an apparent difference in the pharmacokinetics between Canadian and South African children. The derived volumes and clearances in the Canadian children were V1 = 0.81 l/kg, V2 = 1.0 l/kg, Cl1 (systemic clearance) = 0.013 l x kg x min, Cl2 = 0.030 l x kg x min. The intersubject variabilities for V1, V2, and Cl1 were 45%, 38%, and 22%, respectively. Plasma concentrations in South African children were 29% less than in Canadian children. The volumes and clearances in the South African children were 29% larger. The terminal half-life was 110 min (1.8 h). Median absolute prediction error for the two-compartment mammillary model was 18%. Heart rate and systolic blood pressure decreased with time and with increasing doses of dexmedetomidine. Respiratory rate and oxygen saturation (in air) were maintained. Sedation was transient. The pharmacokinetics of dexmedetomidine in children are predictable with a terminal half-life of 1.8 h. Hemodynamic responses decreased with increasing doses of dexmedetomidine. Respiratory responses were maintained, whereas sedation was transient.