Neuromuscular Blocking and Reversal Agents

Question 1

Prejunctional acetilcoline receptors are activated by ACh and are believed to function in a positive-feedback control system that serves to maintain the availability of ACh when demand for it is high. They are involved with the mobilization of ACh, but not the actual process of its release.
This refers to which kind of acetilcoline receptor?

Answer 1

Nicotinic

Question 2

Why nondepolarizing NMBAs cause a fade in response to high frequency repetitive stimulation?

Answer 2

Presynaptic receptors, aided by calcium, facilitate replenishment of the motor nerve terminal. In addition to being stimulated by ACh, they are stimulated by SCh and neostigmine and depressed by small doses of nondepolarizing NMBAs. Inhibition of these presynaptic nAChRs explains the fade in response to high-frequency repetitive stimulation such as tetanic or even train-of-four (TOF) stimulation

Question 3

Postjunctional acetilcoline receptor: describe the structure and the local binding of acetilcoline

Answer 3

The postjunctional, mature AChR is an intrinsic membrane glycoprotein with five distinct subunits: two α, one ε, one δ, and one β. The binding sites for acetylcholine are located at the extracellular portion of the α to ε and α to δ subunits.

Each of the subunits contains four helical domains, M1 to M4, that traverse the cell membrane. The ion channel of each subunit has permeability that is equal to that of Na+ and K+, allowing for the flow of ions across the cell membrane along their concentration gradients, with Na+ entering and K+ leaving the muscle cell

Question 4

What are the differences between postjuncional and extrajunctional acetilcoline receptors? When extrajunctional receptors are clinically important?

Answer 4

Extrajunctional receptors are different in structure than the postjunctional nAChRs. They retain the two α-subunits but have γ-unit replacing the ε-subunit. Additionally, whereas postjunctional receptors are confined to the area of the end plate of skeletal muscle that is oppo- II site the prejunctional motor neurons (as a component of the motor end plate), extrajunctional receptors are pre- sent throughout skeletal muscles. Extrajunctional recep- tor synthesis is normally suppressed by neural activity. Prolonged inactivity, sepsis, skeletal muscle denervation, burn injury, or trauma may be associated with a proliferation of extrajunctional receptors. When activated, extrajunctional receptors stay open longer and permit more ions to flow across the muscle cell membrane,2 which in part explains the exaggerated hyperkalemic response when SCh is administered to patients with den- ervation or burn injury. Proliferation of these receptors also accounts for the resistance or tolerance to nondepo- larizing NMBAs, which can be observed in patients with burns or prolonged immobilization.

Question 5

Describe the chemical structure of an NMBA

Answer 5

NMBAs are quaternary ammonium compounds with at least one positively charged nitrogen atom that will bind to one or both of the binding sites present on the postsynaptic cholinergic receptors.

Nondepolarizing NMBAs are either aminosteroid compounds (pancuronium, vecuronium, rocuronium) or benzylisoquinolinium compounds (atracurium, cisatra- curium, mivacurium)

SCh is two molecules of ACh linked by methyl groups

Question 6

What are the phase I and II NMB that can happened with sch? Which dosage can cause phase II NMB?

Answer 6

Depolarizing NMB is also referred to as phase I blockade.

Phase II blockade is present when the postjunctional membrane has become repolarized but still does not respond normally to ACh (desensitization NMB). The mechanism of phase II blockade is unknown but may reflect the development of nonexcitable areas around the end plates that become repolarized but unable to promote the spread of impulses initiated by ACh. With the initial dose of SCh, subtle signs of a phase II blockade begin to appear (fade to tetanic stimulation).

Phase II blockade, which resembles the blockade produced by nondepolarizing NMBAs, predominates when the intravenous dose of SCh exceeds 3 to 5 mg/kg

Question 7

Metabolism of succinylcholine

Answer 7

Hydrolysis of SCh to inactive metabolites is accomplished by plasma cholinesterase (pseudocholinesterase, butyrylcholinesterase), which is produced in the liver. Plasma cholinesterase has an enormous capacity to hydrolyze SCh at a rate rapid enough that only a small fraction of the original intravenous dose of SCh reaches the NMJ. Because plasma cholinesterase is not present at the NMJ, the NMB produced by SCh is terminated by its diffusion from the NMJ into plasma. Therefore plasma cholinesterase influences the duration of action of SCh by controlling the amount of SCh that is hydrolyzed before it reaches the NMJ. Liver disease must be severe before decreases in the synthesis of plasma cholinesterase are sufficient to prolong the effects of SCh. Anticholinest- erases, as used in the treatment of myasthenia gravis, and certain chemotherapeutic drugs (nitrogen mustard, cyclophosphamide) may decrease plasma cholinesterase activity enough that prolonged skeletal muscle paralysis follows the administration of SCh

Question 8

Adverse effects of sccinylcholine

Answer 8

Cardiac dysrhythmias
- Sinusbradycardia
- Junctionalrhythm
- Sinusarrest
Fasciculations
Hyperkalemia
Myalgia
Myoglobinuria
Increased intraocular pressure Increased intragastric pressure Trismus
Malignant hyperthermia

Question 9

Sinus bradycardia, junctional rhythm, and sinus arrest may follow the administration of SCh. These responses are the result of the action of SCh at …

Answer 9

cardiac postganglionic muscarinic receptors

Question 10

Quimical features of nondepolarizing NMBAs

Answer 10

Nondepolarizing NMBAs, because of their quaternary
ammonium groups, are highly ionized, water-soluble compounds at physiologic pH and possess limited lipid solubility. As a result, these compounds cannot easily cross lipid membrane barriers, such as the blood–brain barrier, renal tubular epithelium, gastrointestinal epithelium, or placenta. Therefore nondepolarizing NMBAs do not produce central nervous system effects, renal tubular reabsorption is minimal, oral administration is ineffective, and maternal administration does not adversely affect the fetus.

Question 11

Describe the duration of action (the time required to spontaneously recover to 25% of baseline muscle strength after bolus administration of a NMBA) of rocuronium after administration of 2DE95, 3DE95 e 4DE95

Answer 11

2 DE95 (0,6 mg/kg): 25 - 75min

3 DE95 (0,9 mg/kg): 25 - 88min

4DE95 (1,2 mg/kg): 38 - 150 min

Question 12

Drugs that may enhance the NMB of nondepolarizing NMBAs

Answer 12

volatile anesthetics, aminoglycoside antibiotics, local anesthetics, cardiac antiarrhythmic drugs, dantrolene, magnesium, lithium, and tamoxifen

Question 13

Drugs tha can diminished NMB of nondepolarizing NMBAs

Answer 13

calcium, corticosteroids, and anticonvulsant medications

Question 14

2 relatively common clinical conditions that can cause resistance to the effects of nondepolarizing NMBAs

Answer 14

Burn injury

Skeletal muscles affected by a cerebrovascular accident

Question 15

Cardiovascular effects of nondepolarizing NMBAs

Answer 15

Clinically significant cardiovascular effects are most
likely after the administration of long-acting NMBAs. At
commonly used doses, they cause drug-induced release
of histamine, blockade of cardiac muscarinic receptors,
or blockade of nicotinic receptors at the autonomic ganglia. The intermediate- and short-acting NMBAs, atracurium and mivacurium, may cause transient hypotension
after the rapid administration of relatively large doses
[>0.45 mg/kg (2.5 × ED95) and 0.2 mg/kg (2.5 × ED95),
respectively]. The relative magnitude of circulatory
effects varies from patient to patient and depends on
factors such as underlying autonomic nervous system activity, blood volume status, preoperative medication,
medications administered for induction and maintenance
of anesthesia, and concurrent medication therapy

Question 16

Describe the Perioperative Anaphylaxis Grading System by Rose and colleagues

Answer 16

Grade A - Moderate: Measurable derangements in one of more major organ systems; non–life threatening;
Cardiovascular: hypotension, tachycardia or bradycardia, arrhythmia;
Respiratory: cough, wheeze, difficult ventilation, oxygen desaturation, difficulty swallowing, rhinorrhea;
Other: change in LOC, agitation, GI upset

B - Life-threatening: Cardiovascular and/or respiratory derangement that is life-threatening
Cardiovascular: systolic blood pressure <60 mm Hg, life-threatening tachyarrhythmia or
bradyarrhythmia;
Respiratory: oxygen saturation <90%, inspiratory pressures >40 cm H2O, severe difficulty inflating the lungs, airway angioedema;

C - Cardiac arrest with or without
respiratory arrest:
Cardiac and/or respiratory arrest
Cardiovascular: cardiac arrest
Respiratory: respiratory arrest or complete failure of ventilation

Question 17

Pancuronium features

Answer 17

Pancuronium is a bisquaternary aminosteroid nondepolarizing NMBA with an ED95 of 70 μg/kg; it has an onset of action of 3 to 5 minutes and a duration of action of 60 to 90 minutes. An estimated 80% of a single dose of pan- curonium is eliminated unchanged in urine. In the presence of renal failure, plasma clearance of pancuronium is decreased 30% to 50%, resulting in a prolonged duration of action. An estimated 10% to 40% of pancuronium undergoes hepatic deacetylation to inactive metabolites, with the exception of 3-desacetylpancuronium, which has neuromuscular blocking activity and is approximately 50% as potent as pancuronium.
Pancuronium typically produces a 10% to 15% increase in heart rate, mean arterial pressure, and car- diac output after administration of an intubating dose (1.4 × ED95). The increase in heart rate reflects pancuro- nium-induced selective blockade of cardiac muscarinic receptors, principally in the sinoatrial node.

Question 18

Vecuronium features

Answer 18

Vecuronium is a monoquaternary aminos- teroid nondepolarizing NMBA with an ED of 50 μg/kg
95 that has an onset of action of 3 to 5 minutes and a duration of action of 20 to 35 minutes. This NMBA under- goes both hepatic and renal excretion. Metabolites are largely pharmacologically inactive, with the exception of 3-desacetylvecuronium, which is approximately 50% to 70% as potent as its parent compound, vecuronium, and has a longer duration of action than vecuronium. The increased lipid solubility of vecuronium as compared with pancuronium also facilitates its biliary excretion. The effect of renal failure on the duration of action of vecuronium is small, but repeated or large doses may result in prolonged NMB. Vecuronium does not cause adverse circulatory effects

Question 19

Rocuronium features

Answer 19

Rocuronium is a monoquaternary aminos- teroid nondepolarizing NMBA with an ED95 of 0.3 mg/kg that has an onset of action of 1 to 2 minutes and a duration of action of 20 to 35 minutes.

Clearance of rocuronium is largely as an unchanged drug in bile; deacetylation does not occur. Renal excre- tion of the drug may account for as much as 30% of a dose, and administration of this drug to patients in renal failure could result in a longer duration of action, especially with repeated doses or prolonged intravenous infusion

Question 20

Atracuriam features

Answer 20

Atracurium is a bisquaternary benzyliso- quinolinium nondepolarizing NMBA that consists of a mixture of 10 stereoisomers. It has an ED95 of 0.2 mg/kg and an onset of action of 3 to 5 minutes. Like other intermediate-acting NMBAs, its duration of action is 20 to 35 minutes. This NMBA is cleared by Hofmann elimination, which is a chemical process of spontaneous, nonenzymatic degradation at normal body temperature and pH. It is also eliminated through hydrolysis by non-specific plasma esterases, which are different than the plasma cholinesterase that metabolizes SCh and mivacurium, and AChE, which metabolizes ACh. Laudanosine is the major metabolite of both Hofmann degradation and ester hydrolysis. The two routes of metabolism occur simultaneously and are independent of hepatic and renal function. As such, the duration of atracurium-induced NMB is similar in healthy patients and those with absent or impaired renal or hepatic function. Ester hydrolysis accounts for an estimated two-thirds of degraded atracurium. Hofmann elimination accounts for the remaining breakdown of atracurium.
In large doses atracurium can, especially with rapid bolus administration, cause histamine release resulting in transient hypotension and tachycardia. Doses smaller than 2 × ED95 rarely cause histamine release.

Question 21

Cisatracurium features

Answer 21

Cisatracurium is one of the 10 stereoisomers comprising atracurium and, as such, is a benzylisoquinolinium non- depolarizing NMBA. It has an ED95 of 50 μg/kg and an onset of action of 7 and 5 minutes after administration of either 1 × ED95 or 2 × ED95, respectively (reflective of its greater potency). Like atracurium, it has an intermediate duration of action. Cisatracurium is primarily degraded by a spontaneous chemical process—Hofmann elimination. In contrast to atracurium, nonspecific plasma esterases are not involved in its clearance. Because of the organ-independent clearance of cisatracurium, it can, like atracurium, be administered to patients with renal or hepatic failure or advanced age without a change in its duration of action. Cisatracurium is often used in patients undergoing renal transplantation. In contrast to atracurium, cisatracurium does not cause histamine release, so administration of large doses, as are frequently used to shorten its onset of effect, is free of adverse cardiovascular effects.

Question 22

Mivacurium features

Answer 22

Mivacurium is a benzylisoquinolinium nondepolarizing NMBA with an ED95 of 80 μg/kg that has an onset of action of 2 to 3 minutes and a dura- tion of action of 15 minutes.

Mivacurium consists of a mixture of three stereoisomers (a cis-trans, a trans-trans, and a cis-cis isomer), and the two most active isomers are hydrolyzed by plasma cholinesterase at a rate equivalent to 88% that of SCh. Hydrolysis of these two isomers is responsible for the short duration of action of mivacurium. The cis-cis isomer comprises only a small fraction of the mixture of isomers (∼5%), is a relatively impotent NMBA, and has an intermediate duration of action. Because it is metabolized by plasma cholinesterase, the clearance of mivacurium is decreased and its duration of action is increased in patients with atypical plasma cholinesterase.
Because of its short duration of action, mivacurium would be an appropriate NMBA for short surgical proce- dures. If used for longer procedures, it should be administered as an infusion.
Like atracurium, rapid administration of large doses of mivacurium can cause histamine release, resulting in transient hypotension and tachycardia.

Question 23

Adequate recovery of muscle strength is defined as …

Answer 23

a TOF ratio (TOFR), measured at the adductor pollicis, of 0.9 (90%)

T4/T1 = 0,9

Question 24

In volunteers even a TOFR <0.9 is associated with … and, in patients, is associated with

Answer 24

impaired ability to swallow, increased incidence of aspiration and decreased hypoxic drive to breathe;
facial weakness; diplopia;

decreased patient satisfaction with their postoperative experience, increased respiratory complications, and death

Question 25

Tidal volume is generated by the diaphragm, which is resistant to NMB, and patients can generate a tidal volume of 300 mL even when profoundly paralyzed. To paralyze the diaphragm, patients must have a profound level of NMB and a post tetanic count of …

Answer 25

3 to 5

Question 26

Clinicians with a high level of expertise can differentiate the muscle contraction of the first and the fourth stimulus of the TOF even with an TOFR > 0,6

T or F

Answer 26

F

Clinicians cannot, regardless of their level of expertise, reliably detect anything less than 60% fade in the TOFR. Even with a TOFR of 0.4, the four responses to ulnar nerve stimulation may look and feel as if they are all the same

Question 27

Applications and limitations of double burst stimulation

Answer 27

Double burst stimulation of the ulnar nerve may improve the clinician’s ability to detect more subtle degrees of neuromuscular block. It allows detection of 40% fade between the first and the second response (the equivalent of a TOFR of 0.6). Double burst stimulation (two bursts of three electrical stimulations separated by 750 ms) is perceived by the observer as two separate twitches, eliminating some of the challenges in interpreting the TOFR. The observer’s ability to detect a TOFR less than 0.4 is improved with double burst stimulation, but the ability to conclude that the TOF ratio is greater than 0.9, or even 0.7, is still not ensured

Question 28

How to measured profound paralysis?

Answer 28

Post tetanic stimulation

Profound paralysis that is too deep to be measured by TOF stimulation can be assessed by the post tetanic count. This depth of block is observed after administration of an intubating dose of NMBA, where the TOF count is zero. Applying a tetanic stimulus (50 Hz for 5 seconds) and observing the response to single twitch at 1 Hz that is begun 3 seconds after the tetanic stimulation allows for these profound depths of NMB to be quantified

Question 29

For the intermediate-acting NMBAs, once the number of post tetanic responses is 3, the first twitch in the TOF will appear in approximately …, and once the post tetanic response is 10, the first response to TOF stimulation should reappear in …

Answer 29

10 minutes

1 to 2 minutes

Question 30

Factors That Increase Difficulty of NMB Reversal

Answer 30

• Intensity of depth of NMB at the time that the pharmacologic antagonist is administered
• Dose of the reversal agent
• Rate of spontaneous recovery from the NMBA
• Patient temperature
• Electrolyte abnormalities
• Concomitant medications
• Presence of significant concentrations of the volatile anesthetic

Question 31

Bolus doses of either neostigmine or edrophonium result in peak plasma concentrations within … minutes that decrease rapidly, followed by a slower elimination phase.

Anticholinesterases are eliminated through …

In patients with renal failure where the duration of action of NMBAs may be increased, clearance of anticholinesterases is … and their elimination half-life …, making dose adjustment of anticholinesterases in patients with renal dysfunction …

Answer 31

5 to 10

active secretion by the kidneys

also reduced

increased

unnecessary

Question 32

During a steady-state infusion of NMBA, the onset of action of edrophonium is … minutes and that of neostigmine is … minutes

Answer 32

1 to 2

7 to 11

Question 33

The sugammadex:rocuronium complex is eliminated through …

Answer 33

the kidney

Question 34

The sugammadex:rocuronium complex is eliminated through …

Answer 34

the kidney

Question 35

Adverse effects of sugammadex

Answer 35

Nausea and vomiting
Dry mouth
Tachycardia, bradycardia
Dizziness
Cough
Anxiety, depression
Hypotension, hypertension
Myalgias
Headache

Question 36

Effects of sugammadex in the coagulation system

Answer 36

Sugammadex can cause a dose- dependent, transient prolongation of activated partial thromboplastin time (aPTT) and prothrombin time (PT; international normalized ratio [INR]); however, it does not increase the risk of bleeding