Current Pharmaceutical Design - Volume 25, Issue 19, 2019

The prevalence of obesity is increasing globally. Rational perioperative anesthetic drug selection and administration require knowledge of how obesity interacts with those drugs. In this review, we summarize different aspects of the anesthetic agents, including pharmacokinetics (PK), pharmacodynamics (PD) and clinical application of the most commonly used medications with particular focus on the enhanced recovery of the obese patient.

Multimodal, non-opioid based analgesia has become the cornerstone of ERAS protocols for effective analgesia after spinal surgery. Opioid side effects, dependence and legislation restricting long term opioid use has led to a resurgence in interest in opioid sparing techniques. The increasing array of multimodal opioid sparing analgesics available for spinal surgery targeting novel receptors, transmitters, and altering epigenetics can help provide an optimal perioperative experience with less opioid side effects and long-term dependence. Epigenetic mechanisms of pain may enhance or suppress gene expression, without altering the genome itself. Such mechanisms are complex, dynamic and responsive to environment. Alterations that occur can affect the pathophysiology of pain management at a DNA level, modifying perceived pain relief. In this review, we provide a brief overview of epigenetics of pain, systemic local anesthetics and neuraxial techniques that continue to remain useful for spinal surgery, neuropathic agents, as well as other common and less common target receptors for a truly multimodal approach to perioperative pain management.

Vasodilatory shock is a life-threatening syndrome in critically ill patients and is characterized by severe hypotension and resultant tissue hypoperfusion. This shock state requires the use of vasopressor agents to restore adequate vascular tone. Norepinephrine is still recommended as first-line vasopressor in the management of critically ill patients suffering from severe vasodilation. In the recent time, catecholaminergic vasopressor drugs have been associated with possible side effects at higher dosages. This so-called catecholamine toxicity has focused on alternative noncatecholaminergic vasopressors or the use of moderate doses of multiple vasopressors with complementary mechanisms of action. Besides vasopressin and terlipressin, angiotensin II may be a promising drug for the management of vasodilatory shock. In addition, adjunctive drugs, such as hydrocortisone, methylene blue or ascorbic acid can be added to conventional vasopressor therapy. The objective of this review is to give an overview of the current available vasopressor agents used in vasodilatory shock. A thorough search of PubMed was conducted in order to identify the majority of studies related to the subject. Data on the outcome of several drugs and future perspective of possible management strategies for the therapy of vasodilatory shock are discussed.

Sugammadex is a reversal agent that was engineered to reverse the effects of aminosteroid muscle relaxants. It is a modified gamma-cyclodextrin, i.e. a large glucose molecule bound in a ring-like structure. Sugammadex, when injected intravenously, creates a concentration gradient favoring the movement of aminosteroid muscle relaxants from the neuromuscular junction back into the plasma, and then encapsulates the aminosteroid muscle relaxants within its inner structure by forming tight water-soluble complexes. The dissociation of the aminosteroidal muscle relaxant from the post-synaptic acetylcholine receptors is responsible for the termination of neuromuscular blockade. This review article presents the current indication, mechanism of action, limitations, side effects and contraindications of sugammadex. An overview of monitoring of the adequacy of reversal of aminosteroid muscle relaxants with sugammadex is presented. Moreover, the use of sugammadex in special situations, including “cannot intubate cannot oxygenate” scenarios is also described.

There is an increased use of oral anticoagulants for the prevention of venous and arterial thrombosis. Vitamin-K antagonists have been used for decades as the main oral anticoagulants but they have the draback a complex therapeutic management, slow onset of action and by a different oral intake caused by dietary vitamin K intake. New non-vitamin K antagonist oral anticoagulants (NOACs) have been developed to overcome the limitations of warfarin. Their management is easier as it requires a fixed daily dose without coagulation monitoring. Although their therapeutic profile is safe, proper attention should be paid in case of unexpected need for the reversal of their coagulation effect and in case a patient needs to have a scheduled surgery. For non-acute cardiac surgery, discontinuation of NOACs should start at least 48 hours prior surgery. Intracranial bleedings associated with NOACs are less dangerous comparing to those warfarin-induced. NOACs need to be stopped ≥24 hours in case of elective surgery for low bleeding-risk procedures and ≥48 hours for high bleeding-risk surgery in patients with normal renal function and 72 hours in case of reduced CrCl < 80. The therapy with NOACs should be resumed from 48 to 72 hours after the procedure depending on the perceived bleeding, type of surgery and thrombotic risks. There are some available NOAC reversal agents acting within 5 to 20 minutes. In case of lack of reversal agent, adequate diuresis, renal replacement therapy and activated charcoal in case of recent ingestion should be considered.

Aim: Pharmacologic agents with procoagulant effects and antidotes against antithrombotic drugs play an important role in the prevention and management of perioperative coagulopathic bleeding. The aim of this narrative review is knowledge transfer from new and renewed hemostatic agents to anesthesiologists and other physicians involved in perioperative medicine. Methods: The literature search was performed on PubMed and the Summaries of Product Characteristics of 6 pharmacologic agents of interest: fibrinogen concentrate, vonicog alfa, susoctocog alfa, idarucizumab, andexanet alfa, and argatroban. Results and Discussion: This review highlights renewed interest in fibrinogen concentrate, an old prohemostatic drug, in correcting hypofibrinogenemia which is a leading pathomechanism of perioperative bleeding. This review describes clinically relevant aspects for brand new recombinant prohemostatic drugs for their use in critical clinical situations: vonicog alfa for the prevention and correction of bleeding in von Willebrand syndrome, and susoctocog alfa in acquired hemophilia A. Clinical experience and increasing evidence broadened the field of applications of the old antithrombotic drug argatroban to heparin resistance. New antidotes against new antithrombotic agents revolutionized the safety of chronic antithrombotic therapy in the emergency situations of acute and trauma surgery. Information on dosing and handling of new hemostatic drugs is summarized. Conclusion: New and potent hemostatic agents exist for perioperative use and may enrich the armamentarium of anesthesiologists. Implementation into clinical practice requires their availability and user knowledge. Sustainability of these new drugs depends on post-licensing research, cost-effectiveness, and clinical experience.

Despite the long history of paediatric anaesthesia, there is still much to be discovered regarding how exposure to anaesthesia affects the developing brain. Given that commonly used anaesthetic agents are thought to exert their effect via N-Methyl-D-Aspartate (NMDA) and gamma-aminobutyric acid A (GABAA) receptors, it is biologically plausible that exposure during periods of vulnerable brain development may affect long term outcome. There are numerous animal studies which suggest lasting neurological changes. However, whether this risk also applies to humans is unclear given the varying physiological development of different species and humans. Human studies are emerging and ongoing and their results are producing conflicting data. The purpose of this review is to summarize the currently available evidence and consider how this may be used to minimize harm to the paediatric population undergoing anaesthesia.

Diabetes Mellitus (DM) is now a well-known factor which initiates many metabolic derangements in various tissues and organs including liver, muscle, pancreas, adipose tissue, cardiovascular and nervous system. Cardiovascular complications are the most crucial , and their effects are so intensive that their derangement leads to cardiac failure even in the absence of ischemic heart diseases. This entity of cardiac pathology in DM is often regarded as diabetic cardiomyopathy (DCM). Recently, many plant-derived drugs have been tested to control and alleviate DCM. Wogonin is one of the drugs the characteristics of which have been deeply studied. Wogonin is a flavonoid having yellow color pigment in their leaves and is obtained from the roots of plant Scutellaria Baicalensis Georgi. Wogonin has long been used as an active anti-cancer drug in Chinese medicine practice. In recent past wogonin has shown to possess notable anti-inflammatory, and anti-allergic properties. Wogonin has demonstrated to possess anti-oxidant, anti-viral, anti-inflammatory and also anti-thrombotic properties. Wogonin has shown to alleviate apoptosis, and ER stress in the cells and this property can also be used in the treatment of cardiovascular diseases. Notably, wogonin has been documented to have an extensive margin of safety as well as displays little or no organ toxicity following extended intravenous administration. In this review, we discuss recently discovered therapeutic potential of wogonin in the treatment of DCM.

The prevalence of neurodegenerative disorders characterized by the loss of neuronal function is rapidly increasing. The pathogenesis of the majority of these diseases is not entirely clear, but current evidence has shown the possibility that autophagy, apoptosis, inflammation and oxidative stress are involved. The present review summarizes the therapeutic effects of resveratrol on neurodegenerative disorders, based on the especially molecular biology of these diseases. The PubMed, Cochrane, Web of Science and Scopus databases were searched for studies published in English until March 30th, 2019 that contained data for the role of inflammation, oxidative stress, angiogenesis and apoptosis in the neurodegenerative disorders. There are also studies documenting the role of molecular processes in the progression of central nervous system diseases. Based on current evidence, resveratrol has potential properties that may reduce cell damage due to inflammation. This polyphenol affects cellular processes, including autophagy and the apoptosis cascade under stressful conditions. Current evidence supports the beneficial effects of resveratrol on the therapy of neurodegenerative disorders.

Background: Isoproterenol (ISO) is a non-selective β-adrenergic agonist. Our aims were to investigate the autophagy and cell death pathways including apoptosis and necrosis in ISO-induced cardiac injury in a dosedependent manner. Methods: Male Sprague-Dawley rats were treated for 24 hours with I. vehicle (saline); II. 0.005 mg/kg ISO; III. 0.05 mg/kg ISO; IV. 0.5 mg/kg ISO; V. 5 mg/kg ISO; VI. 50 mg/kg ISO, respectively. Hearts were isolated and infarct size was measured. Serum levels of Troponin T (TrT), lactate dehydrogenase (LDH), creatine kinase isoenzyme MB (CK-MB) were measured. TUNEL assay was carried out to monitor apoptotic cell death and Western blot was performed to evaluate the level of autophagic and apoptotic markers. Results: Survival rate of animals was dose-dependently decreased by ISO. Serum markers and infarct size revealed the development of cardiac toxicity. Level of Caspase-3, and results of TUNEL assay, demonstrated that the level of apoptosis was dose-dependently increased. They reached the highest level in ISO 5 and it decreased slightly in ISO 50 group. Focusing on autophagic proteins, we found that level of Beclin-1 was increased in a dose-dependent manner, but significantly increased in ISO 50 treated group. Level of LC3B-II and p62 showed the same manner, but the elevated level of p62 indicated that autophagy was impaired in both ISO 5 and ISO 50 groups. Conclusion: Taken together these results suggest that at smaller dose of ISO autophagy may cope with the toxic effect of ISO; however, at higher dose apoptosis is initiated and at the highest dose substantial necrosis occurs.

Background: Animal studies on cardiac arrest found that a combination of epinephrine with esmolol attenuates post-resuscitation myocardial dysfunction. Based on these findings, we hypothesized that esmololepinephrine combination therapy would be superior to a reported cardioprotective esmolol therapy alone in a mouse model of myocardial ischemia and reperfusion (IR) injury. Methods: C57BL/6J mice were subjected to 60 min of myocardial ischemia and 120 min of reperfusion. Mice received either saline, esmolol (0.4 mg/kg/h), epinephrine (0.05 mg/kg/h), or esmolol combined with epinephrine (esmolol: 0.4 mg/kg/h or 0.8 mg/kg/h and epinephrine: 0.05 mg/kg/h) during reperfusion. After reperfusion, infarct sizes in the area-at-risk and serum cardiac troponin-I levels were determined. Hemodynamic effects of drugs infused were determined by measurements of heart rate (HR) and mean arterial blood pressure (MAP) via a carotid artery catheter. Results: Esmolol during reperfusion resulted in robust cardioprotection (esmolol vs. saline: 24.3±8% vs. 40.6±3% infarct size), which was abolished by epinephrine co-administration (38.1±15% infarct size). Increasing the esmolol dose, however, was able to restore esmolol-cardioprotection in the epinephrine-esmolol (18.6±8% infarct size) co-treatment group with improved hemodynamics compared to the esmolol group (epinephrine-esmolol vs. esmolol: MAP 80 vs. 75 mmHg, HR 452 vs. 402 beats/min). Conclusion: These results confirm earlier studies on esmolol-cardioprotection from myocardial IR-injury and demonstrate that a dose optimized epinephrine-esmolol co-treatment maintains esmolol-cardioprotection with improved hemodynamics compared to esmolol treatment alone. These findings might have implications for current clinical practice in hemodynamically unstable patients suffering from myocardial ischemia.