|Year : 2020 | Volume
| Issue : 3 | Page : 110-118
Airway effects of anaesthetics and anaesthetic adjuncts: What's new on the horizon?
Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
|Date of Submission||09-Nov-2020|
|Date of Acceptance||28-Nov-2020|
|Date of Web Publication||25-Dec-2020|
Dr. Jyothsna Manikkath
Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal - 576 104, Karnataka
Source of Support: None, Conflict of Interest: None
The use of drugs for airway control has its beginnings in medical anaesthesia. Since then, the 'airway effects' of pharmacological agents have sometimes been a matter of concern, while at other times a boon for the clinician. While several effects of agents on airway function are 'off-target effects', an understanding of these effects could aid in better choice of the drug to be administered to the patient. At the same time, it will aid the drug development scientist in selecting and optimising drug candidates. This review details the developments in the pharmacology of drugs that influence airway function.
Keywords: Airway pharmacology, airways, inhaled volatile anaesthetics, intravenous anaesthetics, neuromuscular blocking agents, opioids
|How to cite this article:|
Manikkath J. Airway effects of anaesthetics and anaesthetic adjuncts: What's new on the horizon?. Airway 2020;3:110-8
| Introduction|| |
Airway function is influenced by several pharmacologic agents. These include drugs that are administered for therapeutic action on the airways, and those that are targeted at other organ systems but also affect the airways via multiple mechanisms. Agents of the former category include bronchodilators and those of the latter category include general anaesthetics. While the airway effects are an adverse effect for some of the molecules mandating greater monitoring of the subject, it is a beneficial consequence for the action of other molecules, potentiating the indication for which they are employed. Understanding airway pharmacology is vital for airway management in emergency medicine and perioperative settings. Moreover, most molecules that are currently brought into clinical practice are developed using computational tools to predict and quantify their interactions with biological targets. Oftentimes, molecules are either withdrawn from the market or their development is discontinued due to off-target effects discovered at a late stage in their clinical trials. Therefore, understanding the effects of molecules on the airway in clinical practice will help in optimising the development of new molecular entities and formulations with greater control on their airway effects. This article reviews the developments in the pharmacology of drugs that influence airway function [Figure 1]. The focus is on recent drug approvals and recent findings from preclinical studies, clinical trials and case reports, which might influence the deployment of these agents in clinical practice in the future.
|Figure 1: Overview of effects of different classes of anaesthetics and anaesthetic adjuncts on airway function|
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| Anaesthetics and Sedatives|| |
General anaesthesia is provided primarily using either inhaled or intravenous (IV) anaesthetics. Inhaled volatile anaesthetics are also increasingly being utilised for sedation in the intensive care unit (ICU) settings because of their favourable pulmonary gas exchange profiles and reduction in the time for extubation. Most anaesthetics profoundly depress the activity of striated muscles of the upper airways and smooth muscles of the lower airways. This is manifested by posterior displacement of tongue and obstruction of airways at the oropharyngeal level and by dose-dependent bronchodilation. However, suppression of the muscle tone may contribute to impairments in gas exchange.,,
Volatile anaesthetics such as halothane, sevoflurane and isoflurane are potent bronchodilators. While the dominant mechanism for their bronchodilatory effect is still under investigation, volatile anaesthetics have been found to directly relax airway smooth muscle by reducing the amounts of intracellular calcium. This effect is brought about by the inhibition of protein kinase C, release of calcium from sarcoplasmic reticulum or voltage-dependent calcium channels. They also demonstrate indirect dilatory effect on airways by depressing neural pathways that mediate reflex bronchoconstriction in response to stimuli and modifying β-receptor sensitivity and circulating levels of catecholamines. Moreover, diffusion of the inhaled agent from the lumen of the airways to the smooth muscle has been hypothesised as a mechanism for the in vivo bronchodilatory effects., Further, the recent discovery of sensory receptors (odorant and tastant) on airway smooth muscle and the bronchodilatory effect of volatile odorants open up avenues for further exploring the mechanism of bronchodilation by inhaled volatile anaesthetics.
Halothane, isoflurane and sevoflurane are also the first-line agents in maintaining anaesthesia in the presence of hyperreactive airways. Apart from their bronchodilatory effects, agents such as sevoflurane have also proven to alleviate inflammatory changes to the airway and bronchoconstriction of cholinergic or histaminergic origin and that induced by cardiopulmonary bypass surgery.
In the ongoing COVID-19 pandemic, the effects of volatile anaesthetics on ventilator parameters and survival in critically ill COVID-19 patients with classical acute respiratory distress syndrome are under investigation. A retrospective, observational study has demonstrated the benefit of isoflurane for ICU sedation in these patients. Another clinical trial comparing the effects of sevoflurane, isoflurane and an IV anaesthetic is under Phase III study.
Desflurane, an anaesthetic with low blood solubility, shows considerable variability in airway resistance along with the propensity to induce bronchoconstriction, especially in smokers. A recent report of bronchospasm induced by the combination of desflurane with sugammadex was suspected to be due to the respiratory irritant effect of the former along with the effect on circulating rocuronium by the latter.
However, despite their dilatory effects on the airways, ether-based anaesthetics, mainly isoflurane and desflurane, have demonstrated airway irritation mediated by action on nociceptive tracheobronchial nerve endings. This may manifest as upper airway events such as coughing, laryngospasm and bronchospasm. At equal anaesthetic gas concentration, the irritant effect is found to be higher with desflurane than with isoflurane., While the airway irritation by sevoflurane is minimal, it is implicated in olfactory impairment. Furthermore, in a recent case study, the airway smooth muscle relaxation by sevoflurane was implicated to cause excessive dynamic airway collapse brought about by high inspiratory airway pressures. Previously, isoflurane, sevoflurane and desflurane have shown reduction in bronchial mucus transport velocity and reduced mucociliary clearance. These might contribute to postoperative complications by reducing the ability of airways to clear secretions. However, this effect on mucociliary clearance could be diminished by low-flow anaesthesia at flows between 0.35 and 1 L/min.,
Intravenous formulations of volatile anaesthetics
Recently, there has been concerted research on the development of IV formulations of volatile anaesthetics for both induction and maintenance of anaesthesia., The rationale behind this move is related not only to the airway (via circumvention of airway irritation) but also to other reasons such as hypothesised reduction in time taken for establishing equilibrium in the brain and tissues, consistent anaesthesia, quicker administration than through the lungs and faster recovery than when administered through the inhaled route. As direct IV injection of volatile anaesthetics can be lethal, they are formulated in either lipid emulsions or perfluorocarbon emulsions. Intravenous emulsions of sevoflurane,, and isoflurane, have been tested preclinically primarily on rodent models. While these studies are promising, the efficacy and safety of these formulations have not been investigated in clinical trials. Although these formulations could be efficient anaesthetics, their IV delivery approach could indicate lesser direct action on airway smooth muscle. Therefore, the effect of these formulations on bronchodilation per se requires further investigation.
Most commonly used IV anaesthetics including propofol, barbiturates, etomidate and ketamine affect airway reactivity. While these agents have reigned undisputed in the IV anaesthetic space, new molecular entities and novel derivatives and formulations of existing agents, which can bring about specific advantages over the parent compounds, are under development and include the following:
This is a relatively novel ultra-short-acting benzodiazepine anaesthetic/sedative. Like most other benzodiazepines, it acts as an agonist on GABAA receptors. It is rapidly inactivated by an esterase-mediated metabolism, independent of hepatic or renal function, and is eliminated by first-order kinetics. As a result, it produces both faster onset of action and quicker recovery than midazolam. In comparison with propofol, remimazolam does not produce cardiorespiratory depression. Prolonged infusion or higher doses of this agent do not accumulate in the body or cause extended effects. This drug was under development from the late 1990s (under the code name CNS 7056) and received regulatory approval in 2020 for use in general anaesthesia in adults (Japan) and for procedural anaesthesia (USA). A clinical trial comparing the efficacy and safety of IV remimazolam tosylate versus propofol in patients undergoing colonoscopy investigated the respiratory depressant effect of these two agents. Decreases in respiratory rate and oxygen saturation were significantly lower with remimazolam (P < 0.001) as compared to propofol. During upper gastrointestinal endoscopy, patients who received remimazolam tosylate demonstrated lesser respiratory depression in comparison with patients who received propofol. Previous studies on sheep demonstrated that remimazolam (administered as IV infusion) temporarily reduced respiratory rate to the order of 20%–30% observed at doses 0.074 mg/kg to 4.42 mg/kg. This study noted positive dose–response relationship on arterial carbon dioxide tension with increasing doses of benzodiazepine. Inhaled remimazolam aerosols (10–25 mg/mL solutions) on rodents, either alone or in combination with inhaled remifentanil, did not produce bronchospasm, lung irritation or adverse pulmonary effects. Intranasal remimazolam (10–40 mg) was found to produce 'no abnormal trends' in respiratory rate.
Propofol derivatives (HX0507 and HX0969w)
Although propofol has almost monopolised IV anaesthesia at present, considerable research is being directed towards the development of water-soluble prodrugs of propofol to overcome the issues associated with emulsion-based infusions. HX0507, a water-soluble prodrug of propofol with similar anaesthetic effects, was found in preclinical studies to produce less dose-dependent respiratory depression compared to that of the parent drug. Similar effects were observed in preclinical studies with HX0969w. Moreover, HX0969w gets metabolised to propofol unlike fospropofol disodium (another water-soluble propofol prodrug) which produces a toxic metabolite in vivo.
Alphaxalone is a progesterone analogue that has anaesthetic, along with sedative, anticonvulsant and neuroprotective properties. While alphaxalone was earlier used in clinical practice as a mixture with alphadolone, it was withdrawn due to hypersensitivity reactions (including bronchospasm) to an excipient (viz., Cremophor EL) in the formulation. To overcome this issue, alphaxalone was reformulated with 7-sulfobutylether β-cyclodextrin (13%) for IV anaesthesia. Reformulation of alphaxalone with cyclodextrin was found to improve its therapeutic index compared with the earlier product containing Cremophor EL. In clinical trials, the reformulated product caused lesser upper airway obstruction than propofol emulsion. The different effects on airway patency by the two drugs are suggested to be due to the lack of activity of alphaxalone in the brainstem unlike propofol.
Anaesthetics such as lignocaine, benzocaine, tetracaine, bupivacaine and dyclonine are commonly used locally on mucous membranes of the upper airways during awake intubation and interventions such as bronchoscopy.,, Most local anaesthetics bind to voltage-gated sodium channels and reversibly block nerve conduction, reducing the responsiveness to stimuli that cause bronchospasm. They can attenuate pharyngeal muscle reflex and affect upper airway patency. Local anaesthetics administered in regions other than airways may manifest systemic toxicity if absorbed, requiring oxygenation and ventilation.
This is a combination of bupivacaine (a local anaesthetic) and meloxicam (a nonsteroidal anti-inflammatory drug) that has received European Medicines Agency approval in September 2020 for the management of postoperative pain. It employs a novel tri (ethylene glycol) poly (orthoester) formulation for sustained drug release and analgesia. Nonclinical studies did not reveal systemic toxicity with HTX-011.
| Anaesthetic Adjuvants|| |
Neuromuscular blocking agents
Neuromuscular blocking agents (NMBAs) are employed for muscle relaxation during tracheal intubation and to provide immobilisation during surgery. NMBAs bind to the nicotinic acetylcholine receptor and selectively block neuromuscular transmission. These affect airway function by various mechanisms including dose-dependent release of histamine and binding to muscarinic receptors. Curare, atracurium (including its cis-isomer) and mivacurium are well known for histamine release and associated bronchospasm. Rapacuronium, which was once used in endotracheal intubation, was withdrawn on account of the high incidence of bronchospasm and increased risk of mortality. This agent has high affinity for muscarinic M2 receptors. In the quest for agents without muscarinic M3 effects, novel molecules of chlorofumarate class have been developed and include gantacurium, CW002 and CW011.,
This is an ultrashort acting NMBA with rapid onset and a wide safety margin. It has neuromuscular properties identical to succinylcholine, but without its undesirable side effects. Preclinical studies of this drug on different animal models have revealed the absence of effect on cardiac M2 muscarinic receptors (along with lack of effect on muscarinic M3 receptors), minimal histamine release and no bronchoconstriction.,, This drug abolished laryngospasm in cats and reduced tracheal intubation-induced morbidity in this species. Early clinical trials also indicated the absence of detrimental airway effects. In these trials, histamine release was dose dependent and was observed only at doses of 4 × ED95. However, compared to mivacurium, it has improved margin of safety for histamine release.
This is a structural analogue of gantacurium, differing in a chlorine atom at the fumarate double bond and being symmetrical. It is also rapid acting, producing 100% neuromuscular block in 1 min in preclinical studies., In humans, it was found to be slightly less potent and the onset of neuromuscular block was at 90 s at a dose of 0.14 mg/kg (1.8 × ED95). Both preclinical and human studies revealed absence of histamine release and associated bronchoconstriction with minimal cardiopulmonary effect when administered as a single bolus.
This molecule is a structural analogue of gantacurium, and therefore of CW002 as well. Based on in vitro studies, it has slower L-cysteine adduction and is therefore expected to bring about neuromuscular blockade for longer duration than gantacurium.
Drugs that antagonise neuromuscular blocking agents
Considerable research has been focused on the development of an 'ideal' agent to antagonise neuromuscular blockade to overcome residual effects of NMBAs and ensure complete recovery from muscle relaxation. From physostigmine, neostigmine and its analogues such as edrophonium came into existence. However, even the more commonly used neostigmine presented issues such as postoperative respiratory complications. This led to the development of newer molecules with molecular container-like properties, which produce reversal effects based on chelation and encapsulation of the NMBA from plasma.
Sugammadex sodium (gammacyclodextrin)
Sugammadex sodium is an approved agent (US Food and Drug Administration [USFDA], 2015) for antagonising rocuronium, pancuronium and vecuronium-induced neuromuscular blockade. Chemically, it is a hydrophilic modified cyclodextrin with a lipophilic core. With respect to its effect on the airways, both preclinical and clinical reports are available. When tested on rats, sugammadex administered for antagonism of rocuronium-induced blockade did not elicit changes in genioglossus muscle activity or normal breathing. In the same study, neostigmine administered for the same purpose was found to significantly impair the activity of upper airway dilator muscle. While the muscarinic effects of neostigmine such as bronchospasm, increased airway resistance and increased secretions are well established, sugammadex does not intrinsically possess such properties. A comparator trial of sugammadex and neostigmine on asthmatic individuals undergoing open cholecystectomy revealed that the former (at a dose of 4 mg/kg) was well tolerated in asthmatics. Krause et al. observed sugammadex to decrease the residual postoperative airway failure effect of NMBAs to a greater extent than neostigmine. In yet another clinical trial by McGuire and Dalton, 200 mg of sugammadex administered after prior anaesthesia by a variety of agents produced apparent obstruction of the upper airway or vocal cord adduction which spontaneously resolved within 3 min. This led the researchers to conclude that sugammadex increases upper airway tone. Although the authors acknowledge some limitations in the conduct of their study, their findings warrant caution in the use of sugammadex. A recent case report of bronchospasm induced by a combination of desflurane and sugammadex has been mentioned in an earlier section of this article. Furthermore, sugammadex was approved in the USA after three attempts due to its potential for anaphylaxis and postoperative bleeding. Its use may not be widespread on account of its prohibitive cost, which may come down with the availability of generic versions of this molecule.
This is a modified γ-cyclodextrin derivate akin to sugammadex. Compared to sugammadex, it has lower propensity for adverse effects on account of its reduced binding rate with nontargeted molecules. Phase 1 clinical trial affirms the lack of side effects observable with sugammadex. In this trial, three instances of cough, dizziness and upper respiratory infection were reported, but were believed to be unrelated to the drug. Due to paucity of available literature, the airway effects of adamgammadex cannot be conclusive at present. This agent also is yet to undergo other phases of clinical trials before it becomes available for clinical use.
The laevorotatory enantiomer of cysteine has been reported in preclinical studies to reverse any depth of neuromuscular blockade induced by gantacurium, CW002 and CW011. IV administration of L-cysteine 1 min after any of the above fumarates abolished the block within 3 min. Clinical studies of this 'reversal' agent are yet to be undertaken. Apart from the effect of reversing neuromuscular block, the studies could shed light on potential airway effects of this molecule.
Calabadion-1 and calabadion-2 are the first- and second-generation representatives of this class of 'molecular containers'. They reverse the block produced by rocuronium, cisatracurium and vecuronium. The NMB reversal by calabadion-2 was found to be superior to that produced by sugammadex, which could be related to its higher target-binding affinity. Calabadion-1 is also reported to reverse the respiratory effects of fentanyl in preclinical studies. Specifically, it reversed laryngeal, thoracic and abdominal muscle rigidity induced by fentanyl.
| Opioids|| |
Opioids are a central component in the management of moderate to severe postoperative pain. Conventionally used opioids including morphine and fentanyl produce analgesic effect by binding to central μ-opioid receptors (MORs), followed by a cascade of events. While the analgesia is believed to be primarily through G-protein activation, the recruitment of β-arrestin proteins has been hypothesised to play a role in the development of opioid-related adverse events and opioid-induced respiratory depression (OIRD)., Opioid administration may also lead to inhibition of tachykinin release and other sensory nerve functions. This may reduce airway reactivity.
This is a novel opioid agonist approved for IV administration by the USFDA in August 2020 for the management of moderate to severe acute pain. Unlike morphine which activates both G-protein and β-arrestin pathways, oliceridine is a G-protein-selective μ-agonist and less potent in its β-arrestin recruitment which theoretically would imply lower adverse respiratory events. Studies on rodents found increased therapeutic index for analgesia versus respiratory suppression and sedation for oliceridine, in comparison to morphine. Similarly, clinical trials of oliceridine on pain following abdominoplasty or bunionectomy found reduction in 'respiratory safety burden' (RSB; a novel measure of respiratory compromise) in comparison with morphine., However, this reduction in RSB was statistically significant only at the lowest doses of oliceridine. Moreover, although numerically lower than with morphine, there was a dose-dependent increase in the proportion of patients receiving oxygen or having dosing interruption (DI) with oliceridine. Another recent study employed DI to measure the respiratory safety of oliceridine in comparison with morphine. The investigators reported improvement in the respiratory safety of oliceridine when DI was used as a surrogate for OIRD. Notwithstanding, the US prescribing information for this drug includes, along with other risks, a warning on potential life-threatening respiratory depression. Moreover, concomitant administration of this agent along with benzodiazepines, alcohol or other central nervous system depressants may cause exacerbation of respiratory depression.
SR17018 and PZM21
The concept of biased agonism at MOR without engaging β-arrestin pathway has led to the development of other novel compounds such as SR17018 and PZM21, which are in various stages of development., However, concurrently, newer evidence demonstrated the persistence of respiratory depression in β-arrestin 2 knock-out mouse model and questioned the validity of the biased agonism at MOR. Another study that examined the antinociception and respiratory depression produced by SR17018 and PZM21 suggested low intrinsic affinity of these compounds in all signalling pathways to be the reason for their improved side effect profile in comparison with the conventional opioids. At the time of writing this review, there is no sufficient evidence from these studies to conclude on the pathway behind the observed improvement in side effects with these ligands.
| Drugs for Asthma and Chronic Obstructive Pulmonary Disease|| |
Diseases such as asthma, chronic obstructive pulmonary disease or cystic fibrosis are characterised by heightened airway reactivity. Bronchodilators (muscarinic antagonists, β2 agonists and methylxanthines) and anti-inflammatory agents (corticosteroids) are the mainstay of treatment, with mucolytics and antibiotics assisting the role of other agents. There are various classes of drugs in different stages of development including bitter taste receptor agonists, E-prostanoid receptor-4 agonists, rho kinase inhibitors, pepducins, calcilytics, peroxisome proliferator-activated receptor-γ agonists, relaxin family peptide receptor 1 agonists and phosphodiesterase-4 inhibitors., The presence of these conditions can predispose the individual for perioperative bronchoconstriction, while concomitant administration of the bronchodilators/anti-inflammatory drugs could result in several interactions with anaesthetics and anaesthetic adjuvants, requiring necessary adjustments in the administration of the latter drugs. To address this topic as extensive would be an understatement. It is proposed to cover details of these medications in a review to follow.
| Summary|| |
Development of molecules as drugs involves concerted research effort, and is usually a continuous process, which takes into account any new research or clinical finding. A drug intended for one indication may, or rather will, affect several other systems in the body. Most often, these influences are inadvertent and the very parts of molecular structure which bring about the intended therapeutic effects also produce adverse effects. Sometimes, these events turn out beneficial. When the adverse events are severe on the one hand and unavoidable on the other hand, the only option would be to have sufficient counter treatments available in one's arsenal so as to reduce morbidity and mortality in clinical practice.
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Conflicts of interest
There are no conflicts of interest.
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