Preclinical pharmacology of sugammadex

Since the introduction of nondepolarizing neuromuscular blocking agents, acetylcholinesterase inhibitors have been used to increase the speed of recovery from neuromuscular blockade. The major disadvantages of acetylcholinesterase inhibitors are their lack of activity against profound neuromuscular blockade and their activity outside the neuromuscular junction resulting in unwanted side effects, requiring cotreatment with a muscarinic antagonist. An alternative to acetylcholinesterase inhibitors is the encapsulating agent sugammadex. This agent has been specifically designed to encapsulate the steroidal neuromuscular blocking agents rocuronium and vecuronium. This review describes the effects of sugammadex in in vitro tissue and in vivo animal experiments. The encapsulation approach allows reversal of any degree of neuromuscular blockade because the dose of sugammadex can be adjusted to encapsulate sufficient neuromuscular blocking molecules to cause effective reversal. Because this interaction is a drug-drug interaction, reversal can be achieved very fast but is limited by the circulation time. Sugammadex is also effective against neuromuscular blockade under conditions with reduced acetylcholine release, which potentiate the action of neuromuscular blocking agents. Sugammadex does not cause cholinergic side effects, preventing the need of coadministration of muscarinic antagonists. Because of these properties, sugammadex has the potential to become a very useful drug for the management of neuromuscular blockade.     

Residual neuromuscular blockade in critical care

Neuromuscular blockade is a pharmacological adjunct for anesthesia and for surgical interventions. Neuromuscular blockers can facilitate ease of instrumentation and reduce complications associated with intubation. An undesirable sequela of these agents is residual neuromuscular blockade. Residual neuromuscular blockade is linked to aspiration, diminished response to hypoxia, and obstruction of the upper airway that may occur soon after extubation. If an operation is particularly complex or requires a long anesthesia time, residual neuromuscular blockade can contribute to longer stays in the intensive care unit and more hours of mechanical ventilation. Given the risks of this medication class, it is essential to have an understanding of the mechanism of action of, assessment of, and factors affecting blockade and to be able to identify factors that affect pharmacokinetics.     

Effects of Delphinium alkaloids on neuromuscular transmission.

The Delphinium alkaloids methyllycaconitine (MLA), nudicauline, 14-deacetylnudicauline (14-DN), barbinine, and deltaline were investigated for their effects on neuromuscular transmission in lizards. The substituent at C14 provides the only structural difference among the alkaloids MLA, nudicauline, 14-DN, and barbinine. Deltaline lacks the N-(methylsuccinyl)anthranilic acid at C18 common to the other four alkaloids. Each alkaloid reversibly reduced extracellularly recorded compound muscle action potential (CMAP) amplitudes in a concentration-dependent manner. The IC(50) values for CMAP blockade were between 0.32 and 13.2 microM for the N-(methylsuccinimido)anthranoyllycacotonine-type alkaloids and varied with the C14 moiety; the IC(50) value for deltaline was 156 microM. The slopes of the concentration-response curves for CMAP blockade were similar for each alkaloid except barbinine, whose shallower curve suggested alternative or additional mechanisms of action. Each alkaloid reversibly reduced intracellularly recorded spontaneous, miniature end-plate potential (MEPP) amplitudes. Alkaloid concentrations producing similar reductions in MEPP amplitude were 0.05 microM for 14-DN, 0.10 microM for MLA, 0.50 microM for barbinine, and 20 microM for deltaline. Only barbinine altered the time constant for MEPP decay, further suggesting additional or alternative effects for this alkaloid. MLA and 14-DN blocked muscle contractions induced by exogenously added acetylcholine. All five alkaloids are likely nicotinic receptor antagonists that reduce synaptic efficacy and block neuromuscular transmission. The substituent at C14 determines the potency and possibly the mechanism of nicotinic acetylcholine receptor blockade for MLA, nudicauline, 14-DN, and barbinine at neuromuscular synapses. The lower potency of deltaline indicates that the N-(methylsuccinyl)anthranilic acid at C18 affects alkaloid interactions with nicotinic acetylcholine receptors at neuromuscular junctions.     

New drug sugammadex: a selective relaxant binding agent

Cyclodextrins are molecules with a hollow, truncated cone shape that possess unique lipophilic and hydrophilic properties. These unique properties enable cyclodextrins to engulf and bind lipophilic molecules while maintaining aqueous solubility. Encapsulation of molecules is the principal action of a new drug class, selective relaxant binding agents, which binds and inactivate aminosteroid nondepolarizing muscle relaxants. Sugammadex is the name of a modified cyclodextrin currently in phase 3 studies by Organon International (Oss, The Netherlands), and it may hold promise for a new concept in muscle relaxant reversal. Encapsulation rather than competitive antagonism of neuromuscular blockade may be a future modality of anesthetic practice.     

Muscle relaxant use during intraoperative neurophysiologic monitoring

Neuromuscular blocking agents have generally been avoided during intraoperative neurophysiological monitoring (IOM) where muscle responses to nerve stimulation or transcranial stimulation are monitored. However, a variety of studies and clinical experience indicate partial neuromuscular blockade is compatible with monitoring in some patients. This review presents these experiences after reviewing the currently used agents and the methods used to assess the blockade. A review was conducted of the published literature regarding neuromuscular blockade during IOM. A variety of articles have been published that give insight into the use of partial pharmacological paralysis during monitoring. Responses have been recorded from facial muscles, vocalis muscles, and peripheral nerve muscles from transcranial or neural stimulation with neuromuscular blockade measured in the muscle tested or in the thenar muscles from ulnar nerve stimulation. Preconditioning of the nervous system with tetanic or sensory stimulation has been used. In patients without neuromuscular pathology intraoperative monitoring using peripheral muscle responses from neural stimulation is possible with partial neuromuscular blockade. Monitoring of muscle responses from cranial nerve stimulation may require a higher degree of stimulation and less neuromuscular blockade. The role of tetanic or sensory conditioning of the nervous system is not fully characterized. The impact of neuromuscular pathology or the effect of partial blockade on monitoring muscle responses from spontaneous neural activity or mechanical nerve stimulation has not been described.     

Novel pharmacological approaches for the antagonism of neuromuscular blockade

Gamma cyclodextrin and purified plasma cholinesterase are 2 novel pharmacological agents being investigated as to their suitability for antagonism of neuromuscular blockade. Both of these agents are devoid of cholinergic stimulation and the accompanying side effects because their action is independent of acetylcholinesterase inhibition. Gamma cyclodextrin antagonizes the steroidal neuromuscular blocker rocuronium via the chemical encapsulation of the molecule forming a "host-guest" complex through van der Waals and hydrophobic interactions in the plasma. Encapsulation decreases plasma drug concentrations, shifting the neuromuscular blocking drug molecules from the neuromuscular junction back to the plasma compartment resulting in a rapid recovery of the neuromuscular function. Org 25969, a modified gamma cyclodextrin, will antagonize profound neuromuscular block induced by rocuronium in approximately 2 minutes. A commercial preparation of purified human plasma cholinesterase has been shown to be effective in reversing succinylcholine or mivacurium-induced block. Administration of exogenous plasma cholinesterase also has been shown to be effective in antagonizing mivacurium-induced neuromuscular block, cocaine toxicity, and organophosphate poisoning.     

Characterization of neuromuscular blocking action of piperidine derivatives.

cis and trans forms of 2-methyl-6-n-undecyl piperidines (C-11) are the main constituents of fire ant venom and have been studied for their mechanism of action on the neuromuscular transmission of the nerve-sartorius muscle preparation of frogs. At low concentrations (l times 10(-6)-2 times 10(-5) M), cis- and trans-C-11 irreversibly decreased the amplitude of spontaneous miniature end-plate potentials nerve-evoked end-plate potentials and iontophoretically induced acetylcholine depolarizations without changing the membrane potential. The quantal content and the focally recorded action potentials of nerve terminals remain unchanged. It was concluded that the piperidine derivatives block neuromuscular transmission postsynaptically through a decrease in the sensitivity of the end-plate membrane to acetylcholine. Pretreatment of the end-plate with d-tubocurarine did not effect the blocking action of trans-C-11. In direct binding experiments, trans-C-11 did not compete for the sites occupied by alpha-bungarotoxin, decamethonium, carbamylcholine and d-tubocurarine. These data suggest that trans-C-11 does not bind to the acetylcholine receptor site where the other cholinergic ligands have their affinity. It appears that these piperidine derivatives interfere with the coupling mechanism between acetylcholine-receptor binding and ionic conductance increases.     

Evidence for Antinociceptive Activity of Botulinum Toxin Type A in Pain Management

The neurotoxin, botulinum toxin type A, has been used successfully, in some patients, as an analgesic for myofascial pain syndromes, migraine, and other headache types. The toxin inhibits the release of the neurotransmitter, acetylcholine, at the neuromuscular junction thereby inhibiting striated muscle contractions. In the majority of pain syndromes where botulinum toxin type A is effective, inhibiting muscle spasms is an important component of its activity. Even so, the reduction of pain often occurs before the decrease in muscle contractions suggesting that botulinum toxin type A has a more complex mechanism of action than initially hypothesized. Current data points to an antinociceptive effect of botulinum toxin type A that is separate from its neuromuscular activity. The common biochemical mechanism, however, remains the same between botulinum toxin type A's effect on the motor nerve or the sensory nerve: enzymatic blockade of neurotransmitter release. The antinociceptive effect of the toxin was reported to block substance P release using in vitro culture systems. ¹
The current investigation evaluated the in vivo mechanism of action for the antinociceptive action of botulinum toxin type A. In these studies, botulinum toxin type A was found to block the release of glutamate. Furthermore, Fos, a product of the immediate early gene, c- fos , expressed with neuronal stimuli was prevented upon peripheral exposure to the toxin.
These findings suggest that botulinum toxin type A blocks peripheral sensitization and, indirectly, reduces central sensitization. The recent hypothesis that migraine involves both peripheral and central sensitization may help explain how botulinum toxin type A inhibits migraine pain by acting on these two pathways. Further research is needed to determine whether the antinociceptive mechanism mediated by botulinum toxin type A affects the neuronal signaling pathways that are activated during migraine.     

Influence of calcium antagonist drugs in myasthenia gravis in the elderly

A number of drugs have been reported to cause neuromuscular blockade and/or to increase weakness in myasthenia gravis. We report on two patients, treated with felodipine and nifedipine for arterial hypertension, who presented with an exacerbation of their myasthenia gravis and a myasthenic syndrome or exacerbation of myasthenia gravis, respectively. The mechanism of action of calcium antagonist drugs at the neuromuscular junction is not yet well established, but it could be located at both presynaptic and postsynaptic levels.     

The Mechanisms of Action of Intravenous Immunoglobulin and Polyclonal Anti-D Immunoglobulin in the Amelioration of Immune Thrombocytopenic Purpura: What Do We Really Know?

Intravenous immunoglobulin (IVIg) has been used for more than 25 years to treat an ever-increasing number of autoimmune diseases including immune thrombocytopenic purpura. Although the exact mechanism of action of IVIg has remained elusive, many theories have been postulated, including mononuclear phagocytic system blockade/inhibition, autoantibody neutralization by anti-idiotype antibodies, pathogenic autoantibody clearance due to competitive inhibition of the neonatal immunoglobulin Fc receptor, cytokine modulation, complement neutralization, and immune complex formation leading to dendritic cell priming. Polyclonal anti-D immunoglobulin is a polyclonal IVIg product enriched for antibodies directed to the RhD antigen on red blood cells and that has also been successfully used to treat immune thrombocytopenia in RhD(+) patients. The primary theory to explain polyclonal anti-D immunoglobulin function has classically been mononuclear phagocytic system blockade, although modulation of Fcgamma receptor expression and/or immunomodulation may also play a role. Work using a murine model of immune thrombocytopenic purpura to further our understanding of the mechanism of action of these 2 therapeutic agents is a focus of this article.     

Comparison of train-of-four ratios measured with Datex-Ohmeda’s M-NMT MechanoSensor™ and M-NMT ElectroSensor™

Neuromuscular blockade is usually monitored using train-of-four (TOF) stimulation pattern. A TOF ratio of higher than 90 % is recommended to reduce the risk of adverse effects after anaesthesia. TOF ratio 90 % is used in clinical practice with all different neuromuscular monitors. Kinemyography (KMG) is one commercialized method to obtain numerical TOF values. We compared the KMG data obtained with Datex M-NMT MechanoSensor? module, to the EMG data collected with Datex ElectroSensor?, during clinical anaesthesia. Ipsilateral comparisons of the sensors were performed in 20 female patients during clinical procedures in propofol–remifentanil anaesthesia. After initial bolus dose of rocuronium (0.6 mg/kg), the spontaneous recovery of TOF ratio and T1 % were monitored. KMG gave higher TOF values than EMG. The difference was significant at KMG TOF values of 40 % or higher. After anaesthetic induction, but before administration of rocuronium, both TOF sensor values drifted from the TOF value of 1.0, showing either significant spontaneous fade (T1 > T4) or tendency of reverse fade (T1 < T4). KMG overestimates the recovery from neuromuscular blockade when compared with EMG. KMG and EMG cannot be used interchangeably, and TOF ratio 90 % cannot be considered as adequate level of recovery with all monitoring devices.     

Neurotoxicity of Micrurus altirostris (Uruguayan coral snake) venom and its neutralization by commercial coral snake antivenom and specific antiserum raised in rabbits

In this work, we studied the neuromuscular blockade caused by Micrurus altirostris venom (0.1-10 microg/mL) in indirect stimulated chick biventer cervicis and mouse phrenic nerve-diaphragm preparations and the ability of commercial antivenom (Instituto Butantan) and antiserum raised in rabbits to neutralize neurotoxicity and lethality in chicks and mice (LD(50) 0.042 and 0.255 mg/kg), injected i.m. and i.p., respectively, with venom (5 LD(50)):antivenom or antiserum mixtures (n = 6) of 1:1-1:2.5-1:5-1:10-1:20. The venom caused a complete and irreversible neuromuscular blockade in both preparations, inhibited the acetylcholine and carbachol contractures, without interfering on KCl response. The neuromuscular blockade was not Ca(2+) or temperature-dependent and did not affect the response to direct stimulation. Only a venom:antivenom or antiserum ratio of 1:20 neutralized the neuromuscular blockade in vitro and protected chicks and mice against 5 LD(50) of venom. Our results indicated that Micrurus altirostris venom interferes with postsynaptic neurotransmission and that commercial antivenom and rabbit antiserum have low efficacy in neutralizing the neurotoxicity and lethality of this venom.     

Physiology and biology of neuromuscular transmission in health and disease

The introduction of powerful and contemporary research techniques has allowed for an increasingly detailed understanding of neuromuscular transmission. The classic model of nerve signaling to muscle using acetylcholine has been well described. Newer discovery points toward a more complex signaling system with adaptive receptor physiology and a multifaceted action response scheme for muscle relaxants. Although adding complexity, these newer discoveries help align experimentally derived knowledge with clinical observations. In this review, new concepts relative to neuromuscular transmission in health and disease are discussed, including a detailed discussion of acetylcholine and acetylcholine receptor physiology. Recent elucidations of the pathophysiologic responses to neuromuscular injury and its clinical implications are also detailed.     

Heterotopic ossification due to neuromuscular blocking agent in adult respiratory distress syndrome. A case report

Heterotopic ossification (HO) is the formation of mature bone in soft tissues, which can be seen either in cases of traumatic injury or nontraumatic conditions. HO is more commonly observed after a traumatic event, such as a spinal cord injury or head injury. Although less common, it can also be seen after nontraumatic neurological conditions, such as long term coma or neuromuscular blockade. Patients with adult respiratory distress syndrome (ARDS) are at risk of developing HO, due to a prolonged mechanical ventilation period and exposure to neuromuscular blocking agents. In this case report, the authors describe a 51-year-old woman with ARDS, whose HO developed after long-term sedation with neuromuscular blockade agents.     

Muscle relaxants and reversal agents

This article has discussed the anatomy and physiology of the neuromuscular junction and excitation-contraction coupling. The pharmacokinetics and pharmacodynamics of various depolarizing and nondepolarizing neuromuscular blocking agents were presented. Techniques of reversal and the need for concomitant administration of anticholinergics were discussed. Assessment of the postoperative patient, including types of neuromuscular blockade, criteria for successful extubation, and drugs and physiologic states that could prolong neuromuscular blockade were outlined. Because the recovery room nurse is relied on for continuous assessment of the postoperative patient, it is imperative that the nurse have a comprehensive knowledge of intraoperative factors that relate to the patient's recovery. The recovery room nurse should be an expert in the assessment of postoperative patients.     

Clinical limitations of acetylcholinesterase antagonists

Administration of a nondepolarizing neuromuscular blocking drug (muscle relaxant) is a standard practice in many anesthetic scenarios. These muscle relaxants work by competitive antagonism of the neurotransmitter acetylcholine at nicotinic cholinergic receptors within the neuromuscular junction of skeletal muscle (Martyn et al; Neuromuscular physiology and pharmacology, anesthesia. Edited by RD Miller, Philadelphia, Churchill Livingstone, 2000). At the conclusion of the procedure for which the muscle relaxant was administrated, there will be a greater or lesser degree of residual muscle weakness. It is usually necessary to pharmacologically reverse this residual weakness to restore full function to the patient's muscles. Indeed, failure to reverse neuromuscular block is associated with increased perioperative morbidity and mortality (Arbous et al; Impact of anesthesia management characteristics on severe morbidity and mortality. Anesthesiology 2005;102:257-268; quiz 491-2). Pharmacologic reversal currently relies on the administration of an anticholinesterase drug, which decreases the metabolism of acetylcholine at the neuromuscular junction and allows its concentration to increase and hopefully overcome the effect of the muscle relaxant. This approach to reversal has significant limitations; the mechanism of reversal is indirect, the efficacy is limited and unpredictable, and undesirable autonomic responses occur. This review will address these limitations.     

Residual neuromuscular blockade in the immediate postoperative period.

Neuromuscular blocking agents are among the most potent and dangerous drugs administered in the course of a general anesthetic. Their residual actions can have profound effects on a patient's ability to adequately ventilate. Understanding the basics of their actions and the methods of monitoring the level of neuromuscular blockade will assist the PACU nurse in diagnosing the cause of postoperative muscle weakness and hypoventilation. This article will review the mechanisms of action and monitoring of neuromuscular blocking agents, as well as provide a basic overview of postoperative complications involving hypoventilation and motor weakness.     

Intensive care unit drug use and subsequent quality of life in acute lung injury patients

OBJECTIVE: To examine the relationship between the use of sedative and neuromuscular blocking agents during a patient's intensive care unit (ICU) stay and subsequent measures of health-related quality of life. DESIGN: Cross-sectional mail survey and retrospective medical record abstraction of a prospectively identified cohort of lung injury patients. SETTING: ICUs in three teaching hospitals in a major metropolitan area. PATIENTS: Patients with acute lung injury (n = 24). INTERVENTIONS: None--observational study. MEASUREMENTS AND MAIN RESULTS: Patients' charts were reviewed for those patients returning postdischarge quality-of-life questionnaires. Duration, daily dose, and route of administration for sedatives and neuromuscular blocking agents were abstracted from ICU flow sheets. Relationships among ICU variables (days of sedation, days of neuromuscular blockade, and severity of illness as measured by Acute Physiology and Chronic Health Evaluation III score) and outcomes (symptoms of depression and symptoms of posttraumatic stress disorder) were assessed. Depressive symptoms at follow-up were correlated with days of sedation (p = .007), but not with days of neuromuscular blockade or initial severity of illness. The composite posttraumatic stress disorder symptom impact score was correlated with days of sedation (p = .006) and days of neuromuscular blockade (p = .035), but not with initial severity of illness. There were no significant differences between the frequency of patients reporting a specific posttraumatic stress disorder symptom in the high sedation group and the low sedation group, and there were no significant differences in specific posttraumatic stress disorder symptoms between the group that had received neuromuscular blockade and those who had not. CONCLUSIONS: The use of sedatives and neuromuscular blocking agents in the ICU is positively associated with subsequent measures of depression and posttraumatic stress disorder symptoms 6-41 months after ICU treatment for acute lung injury.     

Comparative antihypertensive effects and tissue distribution of beta adrenergic blocking drugs.

The precise mechanism of the antihypertensive action of beta adrenergic blocking drugs is not known. Both peripheral and central sites of action have been proposed. The comparative antihypertensive actions and tissue distribution of propranolol, pindolol and sotalol were investigated in both normotensive Sprague-Dawley and spontaneously hypertensive rats. From recordings of concurrent changes in blood pressure and heart rate it was observed that oral or subcutaneous administrations of both propranolol and pindolol, but not sotalol, consistently reduced blood pressure and heart rate. Tissue distribution of all three agents was determined after 14 days of treatment. Propranolol and a metabolite were concentrated in the hippocampus whereas pindolol was concentrated in the septum. Significant central concentrations of sotalol were not demonstrable. All three agents produced persistent peripheral beta adrenergic blockade. It is concluded that beta adrenergic blockade may not be the important mechanism of the antihypertensive action of beta adrenergic blocking drugs. A modification of central autonomic control mechanisms is proposed as a possible mechanism of action.