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Korean Journal of Anesthesiology Aug 2019Dexmedetomidine is a potent, highly selective α-2 adrenoceptor agonist, with sedative, analgesic, anxiolytic, sympatholytic, and opioid-sparing properties.... (Review)
Review
Dexmedetomidine is a potent, highly selective α-2 adrenoceptor agonist, with sedative, analgesic, anxiolytic, sympatholytic, and opioid-sparing properties. Dexmedetomidine induces a unique sedative response, which shows an easy transition from sleep to wakefulness, thus allowing a patient to be cooperative and communicative when stimulated. Dexmedetomidine may produce less delirium than other sedatives or even prevent delirium. The analgesic effect of dexmedetomidine is not strong; however, it can be administered as a useful analgesic adjuvant. As an anesthetic adjuvant, dexmedetomidine decreases the need for opioids, inhalational anesthetics, and intravenous anesthetics. The sympatholytic effect of dexmedetomidine may provide stable hemodynamics during the perioperative period. Dexmedetomidine-induced cooperative sedation with minimal respiratory depression provides safe and acceptable conditions during neurosurgical procedures in awake patients and awake fiberoptic intubation. Despite the lack of pediatric labelling, dexmedetomidine has been widely studied for pediatric use in various applications. Most adverse events associated with dexmedetomidine occur during or shortly after a loading infusion. There are some case reports of dexmedetomidine-related cardiac arrest following severe bradycardia. Some extended applications of dexmedetomidine discussed in this review are promising, but still limited, and further research is required. The pharmacological properties and possible adverse effects of dexmedetomidine should be well understood by the anesthesiologist prior to use. Moreover, it is necessary to select patients carefully and to determine the appropriate dosage of dexmedetomidine to ensure patient safety.
Topics: Adrenergic alpha-2 Receptor Agonists; Delirium; Dexmedetomidine; Dose-Response Relationship, Drug; Humans; Hypnotics and Sedatives; Patient Selection
PubMed: 31220910
DOI: 10.4097/kja.19259 -
Minerva Anestesiologica Mar 2015Dexmedetomidine, an alpha-2 agonist approved only for sedation in adult intensive care patients, is increasingly used off-label in- and outside Europe in the pediatric... (Meta-Analysis)
Meta-Analysis Review
Dexmedetomidine, an alpha-2 agonist approved only for sedation in adult intensive care patients, is increasingly used off-label in- and outside Europe in the pediatric setting for various indications such as to prevent agitation, as premedication in the form of intranasal, buccal and oral solution, as adjunct for elective surgery, as sedative for magnetic resonance imaging, as intraoperative analgesia, for extracorporeal shock wave lithotripsy, and as adjuvant to ropi- and bupivacaine for nerve blocks. Dexmedetomidine is also used intravenously at different intensive care units with the purpose of sedation of children. In this paper, we assess 51 minor trials in the form of 44 randomized controlled trials and 7 prospective observational studies in an attempt to update the available evidence on dexmedetomidine use in pediatrics. Furthermore, we discuss its potential indications, benefits and adverse effects. However, it is important to state that much of the existing evidence favoring dexmedetomidine in children is either extrapolated from adult studies or based on small randomized controlled trials and observational studies with their inherent methodological shortcomings and confounding factors. Based on the best current evidence dexmedetomidine is found suitable and safe for various indications. However, in order to discover its full potential, indications, dosing and safety profile for various ages and procedures, it should urgently be examined by conducting good quality pediatric trials. Finally, we provide the readers with guidance on how to apply and dose dexmedetomidine for pediatric sedation and for other indications.
Topics: Adolescent; Adrenergic alpha-2 Receptor Agonists; Child; Child, Preschool; Deep Sedation; Dexmedetomidine; Humans; Hypnotics and Sedatives; Infant; Infant, Newborn; Pediatrics
PubMed: 24824958
DOI: No ID Found -
Drug Design, Development and Therapy 2023Peripheral nerve block technology is important to balanced anesthesia technology. It can effectively reduce opioid usage. It is the key to enhance clinical... (Review)
Review
Peripheral nerve block technology is important to balanced anesthesia technology. It can effectively reduce opioid usage. It is the key to enhance clinical rehabilitation as an important part of the multimodal analgesia scheme. The emergence of ultrasound technology has accelerated peripheral nerve block technology development. It can directly observe the nerve shape, surrounding tissue, and diffusion path of drugs. It can also reduce the dosage of local anesthetics by improving positioning accuracy while enhancing the block's efficacy. Dexmedetomidine is a highly selective drug α-adrenergic receptor agonist. Dexmedetomidine has the characteristics of sedation, analgesia, anti-anxiety, inhibition of sympathetic activity, mild respiratory inhibition, and stable hemodynamics. Numerous studies have revealed that dexmedetomidine in peripheral nerve blocks can shorten the onset time of anesthesia and prolong the time of sensory and motor nerve blocks. Although dexmedetomidine was approved by the European Drug Administration for sedation and analgesia in 2017, it has not yet been approved by the US Food and Drug Administration (FDA). It is used as a non-label drug as an adjuvant. Therefore, the risk-benefit ratio must be evaluated when using these drugs as adjuvants. This review explains the pharmacology and mechanism of dexmedetomidine, the effect of dexmedetomidine on various peripheral nerve block as an adjuvant, and compare it with other types of adjuvants. We summarized and reviewed the application progress of dexmedetomidine as an adjuvant in nerve block and look forward to its future research direction.
Topics: United States; Dexmedetomidine; Adjuvants, Immunologic; Anesthetics, Local; Nerve Block; Adrenergic alpha-2 Receptor Agonists; Peripheral Nerves
PubMed: 37220544
DOI: 10.2147/DDDT.S405294 -
Neurobiology of Learning and Memory Dec 2020The selective norepinephrine (NE) α2A-adrenoceptor (α2A-AR) agonist, guanfacine (Intuniv™), is FDA-approved for treating Attention Deficit Hyperactivity Disorder... (Review)
Review
The selective norepinephrine (NE) α2A-adrenoceptor (α2A-AR) agonist, guanfacine (Intuniv™), is FDA-approved for treating Attention Deficit Hyperactivity Disorder (ADHD) based on research in animals, a translational success story. Guanfacine is also widely used off-label in additional mental disorders that involve impaired functioning of the prefrontal cortex (PFC), including stress-related disorders such as substance abuse, schizotypic cognitive deficits, and traumatic brain injury. The PFC subserves high order cognitive and executive functions including working memory, abstract reasoning, insight and judgment, and top-down control of attention, action and emotion. These abilities arise from PFC microcircuits with extensive recurrent excitation through NMDAR synapses. There is powerful modulation of these synapses, where cAMP-PKA opening of nearby potassium (K) channels can rapidly and dynamically alter synaptic strength to coordinate arousal state with cognitive state, e.g. to take PFC "offline" during uncontrollable stress. A variety of evidence shows that guanfacine acts within the PFC via post-synaptic α2A-AR on dendritic spines to inhibit cAMP-PKA-K channel signaling, thus strengthening network connectivity, enhancing PFC neuronal firing, and improving PFC cognitive functions. Although guanfacine's beneficial effects are present in rodent, they are especially evident in primates, where the PFC greatly expands and differentiates. In addition to therapeutic actions in PFC, stress-related disorders may also benefit from additional α2-AR actions, such as weakening plasticity in the amygdala, reducing NE release, and anti-inflammatory actions by deactivating microglia. Altogether, these NE α2-AR actions optimize top-down control by PFC networks, which may explain guanfacine's benefits in a variety of mental disorders.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Attention Deficit Disorder with Hyperactivity; Cognition; Cognition Disorders; Guanfacine; Humans; Macaca mulatta; Memory, Short-Term; Mice; Nerve Net; Neurons; Prefrontal Cortex; Rats; Synapses
PubMed: 33075480
DOI: 10.1016/j.nlm.2020.107327 -
Molecular Medicine Reports Jul 2020Cardiac dysfunction resulting from sepsis may cause significant morbidity and mortality, and ferroptosis plays a role in this pathology. Dexmedetomidine (Dex), a...
Cardiac dysfunction resulting from sepsis may cause significant morbidity and mortality, and ferroptosis plays a role in this pathology. Dexmedetomidine (Dex), a α2‑adrenergic receptor (α2‑AR) agonist exerts cardioprotective effects against septic heart dysfunction, but the exact mechanism is unknown. In the present study, sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6 mice. Dex and yohimbine hydrochloride (YOH), an α2‑AR inhibitor, were administered before inducing CLP. Then, 24 h after CLP, serum and heart tissue were collected to detect changes of troponin‑I (TN‑I), interleukin 6 (IL‑6), superoxide dismutase (SOD), malonaldehyde (MDA) and glutathione (GSH) levels, and iron release. Ferroptosis‑targeting proteins, apoptosis and inflammatory factors were assessed by western blotting or ELISA. It was found that, 24 h after CLP, TN‑I, a biomarker of myocardial injury, was significantly increased compared with the control group. Furthermore, the levels of MDA, 8‑hydroxy‑2'‑deoxyguanosine and the inflammatory factors IL‑6 and monocyte chemoattractant protein‑1 were also significantly increased. It was demonstrated that treatment with Dex reverted or attenuated these changes (CLP + Dex vs. CLP; P<0.05), but these protective effects of Dex were reversed by YOH. Moreover, CLP significantly decreased the protein expression levels of glutathione peroxidase 4 (GPX4), SOD and GSH. However, CLP increased expression levels of heme oxygenase‑1 (HO‑1), transferrin receptor, cleaved caspase 3, inducible nitric oxide synthase and gasdermin D, and iron concentrations. It was found that Dex reversed these changes, but YOH abrogated the protective effects of Dex (CLP + Dex + YOH vs. CLP + Dex; P<0.05). Therefore, the present results suggested that the attenuation of sepsis‑induced HO‑1 overexpression and iron concentration, and the reduction of ferroptosis via enhancing GPX4, may be the major mechanisms via which Dex alleviates sepsis‑induced myocardial cellular injury.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Dexmedetomidine; Ferroptosis; Heart; Heart Injuries; Male; Mice, Inbred C57BL; Myocardium; Sepsis
PubMed: 32377745
DOI: 10.3892/mmr.2020.11114 -
Handbook of Experimental Pharmacology 2017History suggests β agonists, the cognate ligand of the β adrenoceptor, have been used as bronchodilators for around 5,000 years, and β agonists remain today the... (Review)
Review
History suggests β agonists, the cognate ligand of the β adrenoceptor, have been used as bronchodilators for around 5,000 years, and β agonists remain today the frontline treatment for asthma and chronic obstructive pulmonary disease (COPD). The β agonists used clinically today are the products of significant expenditure and over 100 year's intensive research aimed at minimizing side effects and enhancing therapeutic usefulness. The respiratory physician now has a therapeutic toolbox of long acting β agonists to prophylactically manage bronchoconstriction, and short acting β agonists to relieve acute exacerbations. Despite constituting the cornerstone of asthma and COPD therapy, these drugs are not perfect; significant safety issues have led to a black box warning advising that long acting β agonists should not be used alone in patients with asthma. In addition there are a significant proportion of patients whose asthma remains uncontrolled. In this chapter we discuss the evolution of β agonist use and how the understanding of β agonist actions on their principal target tissue, airway smooth muscle, has led to greater understanding of how these drugs can be further modified and improved in the future. Research into the genetics of the β adrenoceptor will also be discussed, as will the implications of individual DNA profiles on the clinical outcomes of β agonist use (pharmacogenetics). Finally we comment on what the future may hold for the use of β agonists in respiratory disease.
Topics: Adrenergic beta-2 Receptor Agonists; Animals; Asthma; Bronchodilator Agents; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive
PubMed: 27878470
DOI: 10.1007/164_2016_64 -
Advances in Therapy Nov 2021In the absence of head-to-head trials, we performed an indirect treatment comparison of the β-adrenergic agonists vibegron and mirabegron in the treatment of overactive...
BACKGROUND
In the absence of head-to-head trials, we performed an indirect treatment comparison of the β-adrenergic agonists vibegron and mirabegron in the treatment of overactive bladder (OAB).
METHODS
PubMed, Embase, and Cochrane Library were searched for articles related to phase 3, double-blind, controlled trials of vibegron 75 mg and mirabegron 25/50 mg in patients with OAB. Efficacy outcomes included change from baseline at weeks 4, 12, and 52 in mean daily number of total urinary incontinence episodes and micturitions and mean volume voided/micturition. Effect size was computed as placebo-subtracted change from baseline (weeks 4, 12) or active control (tolterodine)-subtracted change from baseline (week 52) for each treatment group. Adverse events (AEs) are presented descriptively.
RESULTS
After removal of duplicates, 49 records were identified, and after screening 9 met inclusion criteria for analysis. Vibegron showed significantly greater reduction in mean daily number of total incontinence episodes than mirabegron 25 mg at week 4, mirabegron 50 mg (weeks 4, 52), and tolterodine (weeks 4, 12) (P < 0.05, each) and significantly greater improvement in volume voided versus mirabegron 25 mg (week 12), mirabegron 50 mg (weeks 12, 52), and tolterodine (week 4) (P < 0.05, each). Confidence intervals of point estimates overlapped zero for all other comparisons of vibegron and mirabegron (25 or 50 mg) or tolterodine, indicating no significant differences between treatments for these time/endpoints. Urinary tract infection, hypertension, and dry mouth were the most commonly occurring AEs for vibegron, mirabegron, and tolterodine, respectively, in the short-term trials; hypertension was the most commonly occurring AE with all three treatments in the long-term trials.
CONCLUSIONS
Vibegron was associated with significant improvement in total incontinence episodes versus mirabegron at 4 and 52 weeks and volume voided at 12 and 52 weeks. Improvement in micturitions was similar between vibegron and mirabegron or tolterodine. Incidence of AEs was generally comparable between vibegron and mirabegron.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Clinical Trials, Phase III as Topic; Double-Blind Method; Humans; Muscarinic Antagonists; Pyrimidinones; Pyrrolidines; Randomized Controlled Trials as Topic; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive
PubMed: 34537953
DOI: 10.1007/s12325-021-01902-8 -
British Journal of Anaesthesia Dec 2019Dexmedetomidine (DEX) is a highly selective alpha2 adrenoceptor agonist with broad pharmacological effects, including sedation, analgesia, anxiolysis, and sympathetic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dexmedetomidine (DEX) is a highly selective alpha2 adrenoceptor agonist with broad pharmacological effects, including sedation, analgesia, anxiolysis, and sympathetic tone inhibition. Here we report a systematic review and meta-analysis of its effects on stress, inflammation, and immunity in surgical patients during the perioperative period.
METHODS
We searched MEDLINE, METSTR, Embase, and Web of Science for clinical studies or trials to analyse the effects of DEX on perioperative stress, inflammation, and immune function.
RESULTS
Sixty-seven studies (including randomised controlled trials and eight cohort studies) with 4842 patients were assessed, of which 2454 patients were in DEX groups and 2388 patients were in control (without DEX) groups. DEX infusion during the perioperative period inhibited release of epinephrine, norepinephrine, and cortisol; decreased blood glucose, interleukin (IL)-6, tumour necrosis factor-α, and C-reactive protein; and increased interleukin-10 in surgical patients. In addition, the numbers of natural killer cells, B cells, and CD4 T cells, and the ratios of CD4:CD8 and Th1:Th2 were significantly increased; CD8 T-cells were decreased in the DEX group when compared with the control group.
CONCLUSIONS
DEX, an anaesthesia adjuvant, can attenuate perioperative stress and inflammation, and protect the immune function of surgical patients, all of which may contribute to decreased postoperative complications and improved clinical outcomes.
Topics: Adrenergic alpha-2 Receptor Agonists; Dexmedetomidine; Humans; Immunity; Inflammation; Intraoperative Complications; Postoperative Complications; Preoperative Period; Stress, Physiological
PubMed: 31668347
DOI: 10.1016/j.bja.2019.07.027 -
Drug Testing and Analysis Feb 2021Higenamine was included in the World Anti-Doping Agency (WADA) Prohibited Substances and Methods List as a β -adrenoceptor agonist in 2017, thereby resulting in its... (Review)
Review
Higenamine was included in the World Anti-Doping Agency (WADA) Prohibited Substances and Methods List as a β -adrenoceptor agonist in 2017, thereby resulting in its prohibition both in and out of competition. The present mini review describes the physiology and pharmacology of adrenoceptors, summarizes the literature addressing the mechanism of action of higenamine and extends these findings with previously unpublished in silico and in vitro work. Studies conducted in isolated in vitro systems, whole-animal preparations and a small number of clinical studies suggest that higenamine acts in part as a β -adrenoceptor agonist. In silico predictive tools indicated that higenamine and possibly a metabolite have a high probability of interacting with the β -receptor as an agonist. Stable expression of human β -receptors in Chinese hamster ovary (CHO) cells to measure agonist activity not only confirmed the activity of higenamine at β but also closely agreed with the in silico prediction of potency for this compound. These data confirm and extend literature findings supporting the inclusion of higenamine in the Prohibited List.
Topics: Adrenergic beta-Agonists; Alkaloids; Animals; Athletic Performance; Doping in Sports; Humans; Performance-Enhancing Substances; Receptors, Adrenergic, beta-2; Tetrahydroisoquinolines
PubMed: 33369180
DOI: 10.1002/dta.2992 -
ELife Aug 2020How the brain dynamics change during anesthetic-induced altered states of consciousness is not completely understood. The α2-adrenergic agonists are unique. They...
How the brain dynamics change during anesthetic-induced altered states of consciousness is not completely understood. The α2-adrenergic agonists are unique. They generate unconsciousness selectively through α2-adrenergic receptors and related circuits. We studied intracortical neuronal dynamics during transitions of loss of consciousness (LOC) with the α2-adrenergic agonist dexmedetomidine and return of consciousness (ROC) in a functionally interconnecting somatosensory and ventral premotor network in non-human primates. LOC, ROC and full task performance recovery were all associated with distinct neural changes. The early recovery demonstrated characteristic intermediate dynamics distinguished by sustained high spindle activities. Awakening by the α2-adrenergic antagonist completely eliminated this intermediate state and instantaneously restored awake dynamics and the top task performance while the anesthetic was still being infused. The results suggest that instantaneous functional recovery is possible following anesthetic-induced unconsciousness and the intermediate recovery state is not a necessary path for the brain recovery.
Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Brain; Consciousness; Dexmedetomidine; Electroencephalography; Humans; Hypnotics and Sedatives; Imidazoles; Macaca; Male; Unconsciousness; Wakefulness
PubMed: 32857037
DOI: 10.7554/eLife.57670