Neuromuscular drugs are chemical agents that are used to alter the transmission of nerve impulses to muscles, causing effects such as temporary paralysis of targeted skeletal muscles. Most neuromuscular drugs are available as quaternary ammonium compounds which are derived from acetylcholine (ACh).[1] This allows neuromuscular drugs to act on multiple sites at neuromuscular junctions, mainly as antagonists or agonists of post-junctional nicotinic receptors.[2] Neuromuscular drugs are classified into four main groups, depolarizing neuromuscular blockers, non-depolarizing neuromuscular blockers, acetylcholinesterase inhibitors, and butyrylcholinesterase inhibitors.[2]
Clinically, neuromuscular drugs are used in anesthesia to cause paralysis of targeted skeletal muscles. It is most commonly applied in endotracheal intubation by reducing the incidence of hoarseness in vocal cord and esophageal injuries.[2] It is also applied to improve surgical operating conditions by aiding mechanical ventilation in patients with lowered lung compliance.[1] Other than surgical indications, neuromuscular drugs can also be indicated for the use of Alzheimer's disease, Parkinson's disease, etc.[3] Common adverse effects of neuromuscular drugs include abnormal heart rate, blood pressure, and cardiac output.[4]
History
Curare, a plant containing paralyzing agents
Curare is an alkaloid poison extracted from native South American plants in the Chondrondendron genus.[5] They were initially used by indigenous groups as a paralyzing agent for hunting. European scientist later discovered that tubocurarine was the major constituent responsible for the paralyzing effect by acting on the neuromuscular junction.[6]
Anasthesiologists Harold Griffith and Enid Johnson first documented the successful use of curare, in a clinical trial to facilitate muscle relaxation in a healthy patient undergoing appendicectomy in 1942.[6] Prior to the use of curare, anesthesiologist required large doses of anesthetic such as chloroform to achieve similar paralyzing effects, hence increased the risk of life-threatening effects in elderly patients who had cardiac complications.[6] Ever since, neuromuscular agents have been commonly used in practice during anesthetic procedures.[5] The clinical trial conducted by Griffith and Johnson also paved the way for discovery of many more neuromuscular drugs for surgical use.[5]
Classification
Neuromuscular blocking agents are classified into the following two groups:
Depolarizing neuromuscular blockers: Depolarizing neuromuscular blockers directly bind to postsynaptic cholinergic receptors of the neuromuscular junction to generate a sustained action potential. This causes prolonged stimulation and desensitization of neuroreceptors, causing skeletal muscle relaxation effects such as paralysis.[1] Depolarizing neuromuscular blockers, notably succinylcholine, tend to be preferred over non-depolarizing neuromuscular blockers due to their long-acting and rapid-onset properties.[1]
Non-depolarizing neuromuscular blockers: Non-depolarizing neuromuscular blockers directly bind to acetylcholine receptors on the postsynaptic neuron, and does not cause depolarization of the neuromusuclar junction. They act as competitive inhibitors to acetylcholine, blocking their binding to acetylcholine receptors on the postsynaptic membrane to inhibit membrane depolarization.[1] Inhibition of neurotransmitter binding in the neuromuscular junction induces paralyzing effects. In comparison to depolarizing neuromuscular blockers, non-depolarizing neuromuscular blockers tend to have slower onset times and shorter duration of actions.[1]
Aside from neuromuscular blocking agents, acetylcholinesterase inhibitors and butyrylcholinesterase inhibitors act on the neuromuscular junction to enhance neurotransmitter transmission in voluntary and involuntary muscles.[7] Additionally, some antibiotics, such as aminoglycosides, may also exert undesired side effects on the neuromuscular junction.[7]
Acetylcholinesterase inhibitors: Acetylcholinesterase inhibitors prevent the degradation of acetylcholine, subsequently increasing its concentration and duration of action in the neuromuscular junction.[8] Acetylcholinesterase inhibitors are primarily used to treat symptoms of dementia, Alzheimer's disease, Parkinson's disease, and myasthenia gravis.[3]
Butyrylcholinesterase inhibitors: Butyrylcholinesterease inhibitors prevent the degradation of butyrylcholine, which increases its concentration and duration of action in the neuromuscular junction. Like acetylcholinesterase inhibitors, butyrylcholinesterase inhibitors are regarded as a therapeutic option for Alzheimer's disease.[9]
Aminoglycosides: Aminoglycosides are frequently used in combinational antibacterial therapies for nosocomial respiratory tract infections, complicated intra-abdominal infections, septicemia, osteomyelitis caused by aerobic gram-negative bacilli, and complicated urinary tract infections.[2] Seven neuromuscular drugs are approved by the US Food and Drug Administration, these drugs include: streptomycin, plazomicin, neomycin, amikacin, tobramycin, gentamicin, and paromomycin.[2] It is clinically proven that aminoglycosides can exert neuromuscular blocking side effects.[10] As aminoglycosides only have neuromuscular blocking side effects, they are not a major class of neuromuscular drugs.
Mechanism of action
Diagram of open and closed state of sodium channel (Gate is voltage-activated, and is turned into the active state when surrounding membrane is depolarized by ion, resting state is reached when membrane repolarizes)
Depolarizing neuromuscular blockers: Depolarizing agents act as agonists for acetylcholine receptors. Succinylcholine is currently the only depolarizing neuromuscular blocking drug that has been placed in ongoing clinical use. Its pharmacological structure resembles two acetylcholine molecules combined through acetate methyl groups.[11] It contains two quaternary ammonium radicals which associate with the two alpha subunits of the nicotinic receptor to cause depolarization.[12] These nicotinic receptors respond to acetylcholine and are located in the central and peripheral nervous system, muscle, and other tissue. They act as the primary receptor in muscle for motor nerve-muscle communication which signals muscle contractions.[13]
Under normal conditions, without the interference of depolarizing neuromuscular blockers, when depolarization is triggered, voltage-gated sodium channels are activated due to sensing the depolarization from the activation of acetylcholine receptors.[12] This causes the rapid opening of the sodium channels, then closure after a brief period, becoming inactivated.[14] The membrane potential is then required to be reset before the reactivation of the sodium channels.[12] This process occurs almost instantly with acetylcholine, within one ms, as it is rapidly hydrolyzed through acetylcholinesterase.
However, when depolarizing neuromuscular blockers are applied, the modified structure of succinylcholine is unable to be hydrolyzed by acetylcholinesterase. This causes the extensive activation of the nicotinic receptors and inactivation of the sodium channels,[12] resulting in the blockage of the junctional transmission between muscles, causing the muscle to not contract and remain flaccid.[14] Contrastingly, prolonged use of succinylcholine may cause a desensitization block to the neuromuscular junction, where acetylcholine receptors are insensitive to the channel opening effect of agonists (e.g., acetylcholine or acetylcholine-agonist drugs) (Refer to adverse reactions of depolarizing neuromuscular drugs below).
Binding site of nicotinic receptor (Succinylcholine binds to two alpha subunits of the nicotinic receptor)
Non-depolarizing neuromuscular blockers: Non-depolarizing agents act as competitive inhibitors for acetylcholine. Upon the binding of non-depolarizing neuromuscular blockers, neurotransmission is reduced.[1] Consequently, depolarizing and muscle-contracting effects are decreased. Non-depolarizing neuromuscular blockers are generally reversible, and hence have no permanent effects on acetylcholine receptors.[1][4]
Unlike depolarizing neuromuscular blockers, non-depolarizing drugs do not produce conformational changes to the receptor.[1] The blockers bind to acetylcholine receptors through a dynamic mechanism, with repeated association and dissociation. Thus, as the concentration of antagonists increases, the concentration of binding subsequently increases.[11] Effective neuromuscular block by non-depolarizing neuromuscular drugs occurs only when 70-80% of acetylcholine receptors are occupied by the drug.[11] This is because at this occupancy rate, junctional potential is unable to reach the threshold value required for muscle contraction.
Diagram of nicotinic receptor (Acetylcholine receptor)
The main difference between the two major classes of neuromuscular blocking agents is their respective reversal process of paralyzing effects. Non-depolarizing blockers are reversed through acetylcholinesterase inhibitor drugs which increase the concentration of acetylcholine.[1] Acetylcholine behaves as competitive antagonists on acetylcholine receptors, reducing the binding of non-depolarizing blockers. Whereas, depolarizing blockers that mimic acetylcholine would have increased pharmacological effects when administered alongside acetylcholinesterase inhibitors.[1] Therefore, inhibition reversal for depolarizing neuromuscular blockers occurs naturally within a specific period, after half-life has been achieved.
Acetylcholinesterase and butyrylcholinesterase inhibitors: Both cholinesterase inhibitors share similar mechanisms of action. The active site of cholinesterase's consists of an anionic site and an esteric site.[3]
Phosphorylation of the anionic site by cholinesterase inhibitors prevents the binding of acetylcholine on acetylcholinesterase and butyrylcholine on butyrylcholinesterase respectively.[3] As a result, acetylcholine and butyrylcholine will accumulate in the neuromuscular junction.[3]
Pharmacokinetics
Depolarizing drug
Succinylcholine:
Succinylcholine chemical structure
The dosage of succinylcholine is patient-specific and determined based on total body weight and their physical condition, thus extensive patient assessment and evaluation are required for accurate calculation. The current recommended dose of succinylcholine indicated for tracheal intubation by the FDA for adults is 1.0-1.5mg/kg.[15] Whereas, studies have shown that low-dose succinylcholine (0.45mg/kg) is suitable for optimal intubation conditions in ASA 3 and 4 emergency non-prepared-patients (A patient with severe systemic disease that is a constant threat to life).[16] This dosage can generate profound blockage within 60 seconds (short onset), quicker than other neuromuscular drugs currently available. Where neuromuscular blockage begins to recover within 3 minutes and is completely recovered within 15 minutes.[17] Estimating the dose higher for intubation is preferred over underdosing, as reasonably higher dose produces similar paralysis with little to no known dose associated risks. Whereas under-dosing has shown inadequate paralysis, creating difficulties whilst performing intubation or other operative procedures.[18]
Atracurium chemical structure
Non-depolarizing drug
Vecuronium chemical structurePancuronium acetylcholine chemical structure
Non-depolarizing neuromuscular blockers are indicated in general anesthesia to facilitate endotracheal intubation, and to aid in surgeries via muscle relaxation.[1] They can be further separated into two classes, benzylisoquinolinium compounds and aminosteroid compounds.
Benzylisoquinolinium compounds, also known as benzylisoquinolines, have a structure of two quaternary ammonium groups linked by a chain of methyl groups.[11] The methyl chain contains one or more chiral groups, leading to the existence of stereoisomers of benzylisoquinolinium drugs.[11] Atracurirum, a bezylisoquinolinium drug, is commonly used in clinical settings.
Atracurium: The recommended clinical dosage of atracurium for adults is to “dose to effect” approach to ensure muscle relaxation.[2] The drug has a relatively intermediate duration of action when compared to other non-depolarizing agents.[2] The drug has an onset of 2 to 3 minutes in adults, and an expected peak effect at 3 to 5 minutes.[2] Recovery is expected to begin within 20 to 35 minutes of the initial dose, but it may take up to 70 minutes to achieve 95% recovery.[2]
On the other hand, aminosteroid compounds have a structure based on androstane, with the addition of ACh-like groups.[11] Vecuronium and pancuronium are the two most common aminosteroid compounds utilized in clinical settings.
Vecuronium and pancuronium: The recommended dosage of vecuronium and pancuronium both vary depending on interpatient variability.[2] These drugs aim to achieve adequate muscle relaxation for surgical procedures to prevent surgical trauma.[2] Vecuronium and pancuronium have an onset of 2 to 5 minutes in adults.[2] The time it takes to recover 25% of neuromuscular control after vecuronium and pancuronium therapy are 25 to 40 minutes and 60 to 80 minutes respectively.[2]
Acetylcholinesterase inhibitor
Donepezil chemical structure
Donepezil: Donepezil is a widely used acetylcholinesterase inhibitor indicated for Alzheimer's disease. The drug can be administered orally or with a transdermal patch. However, the estimated time to peak will differ between both routes of administration. Oral donepezil has a peak concentration time of 3 to 8 hours depending on the dosage, while transdermal donepezil has an expected time to peak at 7 days.[2]
Adverse effects
Depolarizing drug
Succinylcholine: Succinylcholine presents several undesirable side effects which affect its application as it interacts with both muscarinic and nicotinic receptors, due to its acetylcholine-mimicking properties.
Firstly, hyperkalemia is the most seen adverse effect of succinylcholine due to its stimulatory effect of the drug on skeletal muscles. This results in an increase in serum potassium levels as high as 0.5 mEq/L.[19] This increase is clinically insignificant in normal patients but can be detrimental for patients with predisposed hyperkalemia caused by up-regulation of post-junctional acetylcholine receptors. Therefore, succinylcholine use is contraindicated for this category of patients.[20] Further consideration is also required for patients with chronically elevated potassium or traumatic injuries, as there is a high probability of acute hyperkalemia which can lead to dysrhythmia or death.[21]
Secondly, succinylcholine causes the activation of muscarinic receptors in the SA node, causing bradycardia. This effect is especially highlighted in use with patients with high vagal tone (traumatic or young patients). In adults with normal vagal tone, bradycardia has only been reported on repeated incremental dosages of succinylcholine.[22] Anticholinergic drugs such as atropine and glycopyrrolate can be used as secondary therapy in treating or prophylaxis of bradycardia.[22]
Thirdly, succinylcholine use has been associated with postoperative myalgia, where patients often experience muscle pain similar to that of post-exercise muscle pain mainly in the shoulders, neck, neck and upper abdominal muscle the following day after surgery, especially in young healthy patients with greater muscle mass, whereas reports from children, elderly and pregnant woman are less frequent.[23] This is caused by the fasciculations (muscle twitches) that appear in sites such as intercostal muscles, and the diaphragm. These fasciculations are not relieved through analgesics, and in common practice, a sub-paralyzing dose of non-depolarizing neuromuscular blocker is administered a few minutes before succinylcholine administration to reduce visible fasciculation and postoperative myalgia.[24] The use of succinylcholine is therefore also contraindicated in patient with muscle myopathy within 24 to 72 hours post-administration.
Non-depolarizing drug
Atracurium: Atracurium is commonly associated with histamine-related symptoms, most notably flushing and erythema.[25] Less commonly seen adverse effects include urticaria, hypotension, wheezing, tachycardia, bronchospasm, dyspnea, bradycardia, and laryngospasm.[4] Moreover, drops of up to 30 mmHg in mean arterial pressure was also observed within two minutes of administration in some patients.[25] H1 and H2 receptor blocking agents can be used to attenuate the drop in mean arterial pressure.[25] A slow injection speed between 30 and 60 seconds have also proved effective in reducing adverse effects.[4] Furthermore, Atracium produces a toxic metabolite called laudanosine when administered, and can accumulate in patients with impaired renal function. This may lead to potential seizures and epilepsy. Thus, the dosage of the atracium should be compensated for patients with decreased renal functions.
Vecuronium: Most of vecuronium's adverse effects is correlated to the drug's extension of pharmacological effects past the desired time of use.[26] Serious adverse effects include bronchospasm, anaphylaxis, apnea, and prolonged paralysis.[26] In some instances, hypersensitivity-associated histamine release may occur, leading to allergy-like symptoms or severe anaphylaxis in rare cases.[4] Vecuronium has a relatively favourable safety profile when compared to pancuronium or other aminosteroid non-depolarizing drugs.[26]
Pancuronium: Pancuronium produces more significant adverse effects due to the blockade of muscarinic M2 receptors in the atria.[27] Therefore, pancuronium may increase cardiac output, mean arterial pressure, and heart rate.[4] To add on, patients with renal failure may experience a 30-50% decrease in plasma clearance, hence an increase in neuromuscular blockade duration.[27] The use of pancuronium with insufficient anesthetic agents leads to morbidity and psychological trauma.[27]
Acetylcholinesterase inhibitor
Donepezil: Donepezil may exhibit cardiac issues such as hypertension, cardiac arrhythmia, atrioventricular block, and bradycardia due to its vagotonia properties.[2] Common gastrointestinal side effects such as nausea, diarrhea, and vomiting are also associated with donepezil and other acetylcholinesterase inhibitors.[2] Studies have also shown an association of donepezil use and nightmares due to increased activation of the visual cortex during sleep. Patients can be advised to complete their drug regimen in the morning to prevent occurrences of nightmares.[28]
Related Research Articles
Suxamethonium chloride, [Scoline, Sucostrin] also known as suxamethonium or succinylcholine, or simply sux by medical abbreviation, is a medication used to cause short-term paralysis as part of general anesthesia. This is done to help with tracheal intubation or electroconvulsive therapy. It is administered by injection, either into a vein or into a muscle. When used in a vein, onset of action is generally within one minute and effects last for up to 10 minutes.
Pancuronium is an aminosteroid muscle relaxant with various medical uses. It is used in euthanasia and is used in some states as the second of three drugs administered during lethal injections in the United States.
The enzyme cholinesterase (EC 3.1.1.8, choline esterase; systematic name acylcholine acylhydrolase) catalyses the hydrolysis of choline-based esters:
Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage. It is also used in anaesthesia to end the effects of non-depolarising neuromuscular blocking medication. It is given by injection either into a vein, muscle, or under the skin. After injection effects are generally greatest within 30 minutes and last up to 4 hours.
Vecuronium bromide, sold under the brand name Norcuron among others, is a medication used as part of general anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. It is also used to help with endotracheal intubation; however, agents such as suxamethonium (succinylcholine) or rocuronium are generally preferred if this needs to be done quickly. It is given by injection into a vein. Effects are greatest at about 4 minutes and last for up to an hour.
In anaesthesia and advanced airway management, rapid sequence induction (RSI) – also referred to as rapid sequence intubation or as rapid sequence induction and intubation (RSII) or as crash induction – is a special process for endotracheal intubation that is used where the patient is at a high risk of pulmonary aspiration. It differs from other techniques for inducing general anesthesia in that several extra precautions are taken to minimize the time between giving the induction drugs and securing the tube, during which period the patient's airway is essentially unprotected.
Pseudocholinesterase deficiency is an autosomal recessive inherited blood plasma enzyme abnormality in which the body's production of butyrylcholinesterase is impaired. People who have this abnormality may be sensitive to certain anesthetic drugs, including the muscle relaxants succinylcholine and mivacurium as well as other ester local anesthetics.
Tubocurarine is a toxic benzylisoquinoline alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxation during surgery or mechanical ventilation. Safer alternatives, such as cisatracurium and rocuronium, have largely replaced it as an adjunct for clinical anesthesia and it is now rarely used.
Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.
Rocuronium bromide is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia to facilitate tracheal intubation by providing skeletal muscle relaxation, most commonly required for surgery or mechanical ventilation. It is used for standard endotracheal intubation, as well as for rapid sequence induction (RSI).
Atracurium besilate, also known as atracurium besylate, is a medication used in addition to other medications to provide skeletal muscle relaxation during surgery or mechanical ventilation. It can also be used to help with endotracheal intubation but suxamethonium (succinylcholine) is generally preferred if this needs to be done quickly. It is given by injection into a vein. Effects are greatest at about 4 minutes and last for up to an hour.
Mivacurium chloride is a short-duration non-depolarizing neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.
Sugammadex, sold under the brand name Bridion, is a medication for the reversal of neuromuscular blockade induced by rocuronium and vecuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA). It is marketed by Merck.
Doxacurium chloride is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. Unlike a number of other related skeletal muscle relaxants, it is rarely used adjunctively to facilitate endotracheal intubation.
Butyrylcholinesterase, also known as BChE, BuChE, BuChase, pseudocholinesterase, or plasma (cholin)esterase, is a nonspecific cholinesterase enzyme that hydrolyses many different choline-based esters. In humans, it is made in the liver, found mainly in blood plasma, and encoded by the BCHE gene.
Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level and duration of action of acetylcholine in the central nervous system, autonomic ganglia and neuromuscular junctions, which are rich in acetylcholine receptors. Acetylcholinesterase inhibitors are one of two types of cholinesterase inhibitors; the other being butyryl-cholinesterase inhibitors. Acetylcholinesterase is the primary member of the cholinesterase enzyme family.
Gantacurium chloride is a new experimental neuromuscular blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in surgical anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Gantacurium is not yet available for widespread clinical use: it is currently undergoing Phase III clinical development.
Candocuronium iodide is a aminosteroid neuromuscular-blocking drug. Its use within anesthesia for endotracheal intubation and for providing skeletal muscle relaxation during surgery or mechanical ventilation was briefly evaluated in clinical studies in India, though further development was discontinued due to attendant cardiovascular effects, primarily tachycardia that was about the same as the clinically established pancuronium bromide. Candocuronium demonstrated a short duration in the body, but a rapid onset of action. It had little to no ganglion blocking activity, with a greater potency than pancuronium.
Postoperative residual curarization (PORC) or residual neuromuscular blockade (RNMB) is a residual paresis after emergence from general anesthesia that may occur with the use of neuromuscular-blocking drugs. Today residual neuromuscular blockade is defined as a train of four ratio of less than 0.9 when measuring the response to ulnar nerve stimulation at the adductor pollicis muscle using mechanomyography or electromyography. A meta-analysis reported that the incidence of residual neuromuscular paralysis was 41% in patients receiving intermediate neuromuscular blocking agents during anaesthesia. It is possible that > 100,000 patients annually in the USA alone, are at risk of adverse events associated with undetected residual neuromuscular blockade. Neuromuscular function monitoring and the use of the appropriate dosage of sugammadex to reverse blockade produced by rocuronium can reduce the incidence of postoperative residual curarization. In this study, with usual care group receiving reversal with neostigmine resulted in a residual blockade rate of 43%.
Tetanic fade refers to the diminishing muscle twitch response from an evoked potential stimulation of muscle under the effect of either a non-depolarizing neuromuscular blocking agent, or a muscle that is under a phase 2 depolarizing neuromuscular blocking agent.
↑ English BA, Webster AA (January 2012). "Chapter 132 - Acetylcholinesterase and its Inhibitors". In Robertson D, Biaggioni I, Burnstock G, Low PA (eds.). Primer on the Autonomic Nervous System (Thirded.). San Diego: Academic Press. pp.631–633. doi:10.1016/B978-0-12-386525-0.00132-3. ISBN978-0-12-386525-0.
↑ Liu M, Kato M, Hashimoto Y (2001). "Neuromuscular blocking effects of the aminoglycoside antibiotics arbekacin, astromicin, isepamicin and netilmicin on the diaphragm and limb muscles in the rabbit". Pharmacology. 63 (3): 142–146. doi:10.1159/000056125. PMID11598419. S2CID23661013.
1 2 Wider de Xifra EA, Battle AM (1973). "Mechanism of action of succinyl CoA synthetase. The role of CoA". Enzyme. 16 (1): 128–137. doi:10.1159/000459372. PMID4791036.
↑ Schreiber JU, Lysakowski C, Fuchs-Buder T, Tramèr MR (October 2005). "Prevention of succinylcholine-induced fasciculation and myalgia: a meta-analysis of randomized trials". Anesthesiology. 103 (4): 877–884. doi:10.1097/00000542-200510000-00027. PMID16192781. S2CID8897329.
1 2 3 Ritz ML, Derian A (2023). "Atracurium". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID29763171. Retrieved 2023-04-12.
1 2 3 Ramzy M, McAllister RK (2023). "Vecuronium". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID29630195. Retrieved 2023-04-12.
1 2 3 Das GN, Sharma P, Maani CV (2023). "Pancuronium". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID30855929. Retrieved 2023-04-12.
↑ Kumar A, Gupta V, Sharma S (2023). "Donepezil". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID30020629. Retrieved 2023-04-12.
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