Pharmacology of Neuromuscular Blocking Drugs

Question 1

Two different populations of nicotinic acetylcholine receptors exist at the mammalian neuromuscular junction. In the adult, the nicotinic acetylcholine receptor at the postsynaptic (muscular) membrane is composed of … subunits, while the fetal (immature) receptor is composed of …
The presynaptic (neuronal) nicotinic receptor is a pentameric complex composed of … subunits.

Answer 1

α2βδε

α2βγδ

α3β2

Question 2

Composition of the nicotinic acetylcholine receptor (nAChR) in the end plate surface of adult mammalian muscle: N termini of two subunits cooperate to form two distinct binding pockets for acetylcholine. These pockets occur at the … and the … subunit interface. The … membranespanning domain of each subunit lines the ion channel.

The doubly liganded ion channel has equal permeability to …;
… contributes approximately 2.5% to the total permeability.

Answer 2

ε-α

δ-α

M2

sodium (Na) and potassium (K)

calcium (Ca)

Question 3

Succinylcholine, a depolarizing NMBD, produces prolonged depolarization of the end plate region, which is similar to, but
more persistent than, the depolarization induced by acetylcholine.
This mechanism results in … .
The end results are failure of action potential generation and neuromuscular blockade

Answer 3

(1) desensitization of the nAChR, (2) inactivation of voltage-gated Na+ channels at the neuromuscular junction, and (3) increases in K+ permeability in the surrounding membrane

Question 4

The fetal nAChR is a low-conductance channel, in contrast to the high-conductance channel of the adult nAChR and upregulation of nAChRs found in states of functional or surgical denervation is characterized by the spreading of predominantly fetal-type nAChRs. These receptors are … to nondepolarizing NMBDs and are … to succinylcholine

Answer 4

resistant

more sensitive

Question 5

Explain the fade phenomenon observed with non depolarizing NMBDs but not with depolarizing NMBDs.

Answer 5

Prejunctional nicotinic receptors are activated by acetylcholine and function in a positive-feedback control system, which could mediate mobilization of the reserve store into the readily releasable store in
case of high-frequency stimulation; this mobilization serves
to maintain availability of acetylcholine when demand for it
is high (e.g., during tetanic stimulation). These presynaptic
receptors are α3β2 neuronal subtype receptors. Although
most nondepolarizing NMBDs have a distinct affinity for the
α3β2 cholinergic receptor, succinylcholine lacks this affinity.
The action of nondepolarizing versus depolarizing NMBDs at
this neuronal cholinergic receptor explains the typical fade
phenomenon after any nondepolarizing drugs, and the lack
of such effect in the clinical dose range for succinylcholine.

Question 6

The G-protein–coupled muscarinic receptors also are involved in the feedback modulation of acetylcholine release. The prejunctional … receptors are involved in facilitation and inhibition of acetylcholine release, respectively, by modulating Ca2+ influx

Answer 6

M1 and M2

Question 7

All NMBDs contain … compounds and as such are structurally closely related to acetylcholine. Positive charges at the … sites of NMBDs mimic the … atom of acetylcholine and are the structural reason for the attraction of these drugs to muscle- and neuronal-type nAChRs at the neuromuscular junction

Answer 7

quaternary ammonium

quaternary ammonium

quaternary nitrogen

Question 8

How does the neuromuscular blockade induced by succinylcholine is terminated?

Answer 8

Because little or no butyrylcholinesterase is present at the neuromuscular junction, the neuromuscular blockade induced by succinylcholine is terminated by its diffusion away from the neuromuscular junction into the circulation.
Butyrylcholinesterase therefore influences the onset and duration of action of succinylcholine by controlling the rate at which the drug is hydrolyzed before it reaches, and after it leaves, the neuromuscular junction

Question 9

Factors that lower butyrylcholinesterase activity include …

Answer 9

liver disease, advanced age, malnutrition, pregnancy, burns, oral contraceptives, monoamine oxidase inhibitors, echothiophate, cytotoxic drugs, neoplastic disease, anticholinesterase drugs, tetrahydroaminacrine, hexafluorenium, and metoclopramide

Question 10

…, a prodrugof terbutaline, produces marked inhibition of butyrylcholinesterase activity and causes prolongation of succinylcholine-induced blockade.
The β-blocker … inhibits butyrylcholinesterase but causes only a minor prolongation of succinylcholine-induced blockade

Answer 10

Bambuterol

esmolol

Question 11

Explain the relation between the dibucaine number and the atypical butyrylcholinesterase activity.
Describe the limitation of this test

Answer 11

Kalow and Genest discovered a variant that responded to dibucaine differently than it did to normal butyrylcholinesterase. Dibucaine inhibits normal butyrylcholinesterase to a far greater extent than
the abnormal enzyme. This observation led to the establishment
of the dibucaine number. Under standardized test conditions, dibucaine inhibits the normal enzyme by approximately 80% and the abnormal enzyme by approximately 20%.

Although the dibucaine number indicates the genetic makeup of an individual with respect to butyrylcholinesterase, it does not measure the concentration of the enzyme in the plasma substrate. This is determined by measuring butyrylcholinesterase activity in plasma, and it may be influenced by comorbidities, medications, and genotype

Question 12

in a patiente Homozygous atypical for butyrylcholinesterase (E1
aE1), dibucaine number of 20-30, the duration of action of succynilcholine is up to …

Answer 12

4-8 h

Question 13

Cardiovascular effects of succynilcholine

Answer 13

• Sinus Bradycardia: stimulation of cardiac muscarinic receptors in the cardiac sinus node causes sinus bradycardia. This side effect is particularly problematic in individuals with predominantly vagal tone, such as in children who have not received atropine
• Nodal (Junctional) Rhythms: nodal rhythms occur commonly
  following administration of succinylcholine. The mechanism responsible for this likely involves relatively greater stimulation of muscarinic receptors in the sinus node, thus suppressing the sinus mechanism and allowing the emergence of the atrioventricular node as the pacemaker.
• Ventricular Dysrhythmias: under stable anesthetic conditions,
  succinylcholine decreases the threshold of the ventricle to catecholamine-induced dysrhythmias in monkeys and dogs.

Question 14

Describe de hyperkalemia after succynilcholine administration

Answer 14

Administration of succinylcholine to an otherwise
healthy individual increases the plasma K+ levels by approximately 0.5 mEq/dL. Severe hyperkalemia may follow the administration
of succinylcholine to patients with severe metabolic acidosis and hypovolemia (In this situation, the K+ originates from the gastrointestinal tract, rather than from muscle).
Additionally, patients with conditions that result in the proliferation of extrajunctional acetylcholine receptors, such as upper or lower motor denervation, immobilization, burn injuries, and neuromuscular disease, are likely to have an exaggerated hyperkalemic response following the administration of succinylcholine

Question 15

Are succynilcholine contraidicated in eye surgery? Explain

Answer 15

Succinylcholine may cause an increase in intraocular pressure (IOP). The mechanism by which succinylcholine increases IOP has not been clearly defined, but it is known to involve contraction of tonic myofibrils and/or transient dilatation of choroidal blood vessels. Sublingual administration of nifedipine may attenuate the increase in IOP caused by succinylcholine, a finding suggesting a circulatory mechanism.

Despite this increase in IOP, the use of succinylcholine for eye operations is not contraindicated unless the anterior chamber is open

Question 16

Patients with a history of anaphylactic reaction to succinylcholine may exhibit a cross-reaction with other NMBDs

T or F

Answer 16

T

Question 17

The incidence of anaphylactic reactions caused by sucynilcholine may be close to …

Answer 17

0.06%

Question 18

Succinylcholine increases the duration of pancuronium, atracurium and rocuronium

T or F

Answer 18

F

Prior administration of succinylcholine enhances the depth of blockade caused by a subsequent dose of nondepolarizing NMBD. However, the effect on duration of action is variable. Succinylcholine has no effect on the duration of pancuronium, but increases the duration of atracurium and rocuronium. The reasons for these differences are not clear.

Question 19

The etiology of the appearance of fade phenomenon in the TOF response following excessive administration of succinylcholine has been suggested to be …

Answer 19

dependent on a concentration-dependent affinity for succinylcholine to the presynaptic α3β2 neuronal subtype AChR in concentrations exceeding the normal clinical concentration range seen after routine doses

Question 20

Atracurium is a bis-benzyltetrahydroisoquinolinium with isoquinolinium nitrogens connected by a diestercontaining
hydrocarbon chain. The presence (in duplicate) of two-carbon separations between quaternary nitrogen and ester carbonyl renders it susceptible to the … .

The compound can also undergo ester … .

Answer 20

Hofmann elimination reaction

hydrolysis

Question 21

In a Hofmann elimination reaction, a quaternary ammonium group is converted into … through cleavage of a carbon-nitrogen bond. This is a … dependent reaction in which … favor elimination

Answer 21

a tertiary amine

pH- and temperature

higher pH and temperature

Question 22

Cisatracurium, the 1R cis–1′R cis isomer of atracurium, comprises approximately …% of atracurium by weight but more than …% in terms of neuromuscular blocking activity

Answer 22

15

50

Question 23

Mivacurium is metabolized by … to a monoester and a dicarboxylic acid

Answer 23

butyrylcholinesterase

Question 24

The EC50 for almost all non deolarizing NMBDs is …% higher at the diaphragm or larynx than it is at the adductor pollicis.

The reason may be …

Answer 24

50% to 100

higher receptor density, greater release of acetylcholine, or less acetylcholinesterase activity

Question 25

… is the only muscle relaxant that, at equipotent doses, causes greater neuromuscular block at the vocal cords than at the adductor pollicis

Answer 25

Succinylcholine

Question 26

In spite of the relative resistance to NMBDs, the onset of neuromuscular block is significantly faster at the diaphragm and the laryngeal adductors than at the adductor pollicis. Explain the reason

Answer 26

Fisher and associates postulated that more rapid equilibration (shorter effect site equilibration halflife [t½ke0]) of the NMBD between plasma and the effect compartment at these more centrally located muscles was the explanation for this observation. The accelerated rate of equilibrium probably represents little more than differences in regional blood flow. Therefore muscle blood flow (i.e., the rate of drug delivery to the tissue), rather than a drug’s intrinsic potency, may be more important in determining the onset and offset time of nondepolarizing NMBDs. Greater blood flow per gram of muscle at the diaphragm or larynx results in delivery of a higher peak
plasma concentration of drug in the brief period of time before rapid redistribution occurs.

Question 27

Why does a TOF ratio less than 0.9 at the adductor pollicis (with a calibrated neuromuscular monitor) is associated with respiratory complications?

Answer 27

The muscles of the upper airway are particularly sensitive to the effects of muscle relaxants.

A TOF ratio less than 0.9 at the adductor pollicis (with a calibrated neuromuscular monitor) is associated with impaired pharyngeal function, reduced resting tone in the upper esophageal sphincter muscle, and decreased coordination of the muscles involved in swallowing, all of which cause an increased incidence of misdirected swallows, or aspiration.

Question 28

How does residual neuromuscar blockade affect peripheral chemoreceptors?

Answer 28

The increase in ventilation during hypoxia is mainly governed by afferent neuronal input from peripheral chemoreceptors of the carotid body. Acetylcholine is involved in the transmission of afferent neuronal activity from the carotid body to the central nervous system (CNS). Eriksson and associates have shown that partial neuromuscular block (TOF ratio of 0.7) reduces specifically the ventilatory responses to isocapnic hypoxia without altering the response to hypercapnia. The ventilatory response to hypoxia returns to control values after recovery of a TOF ratio to above 0.9. The mechanism behind this interaction seems to be a spontaneous,
reversible depression of carotid body chemoreceptor activity during hypoxia

Question 29

When non depolarizing NMBDs doses are lower than those required to cause 100% neuromuscular blockade, the time required to reach maximum effect is a function of … . It is independent of …

However, if the administered dose is high enough to cause 100% neuromuscular blockade, the time required for maximum block will depend on …

Answer 29

the NMBD and blood flow to the muscles

the dose administered

the dose of NMBD administered

Question 30

Definitions of the Depth of Neuromuscular Block Based
- Intense (profound) block
- Deep block
- Moderate block
- Light (shallow) block
- Minimal block (near recovery)
- Full recovery (normal function)

Answer 30

• Intense (profound) block: Posttetanic Count 0
• Deep block: Posttetanic Count ≥1; TOF 0
• Moderate block: Posttetanic Count NA; TOF 1-3
• Light (shallow) block: Posttetanic Count NA; TOF 4
• Minimal block (near recovery): TOF ratio 0,4 - 0,9
• Full recovery (normal function): TOF ratio ≥0.90-1.0

Question 31

Rocuronium is eliminated primarily by the …, with a small fraction (≈10%) eliminated in the …

Answer 31

liver (biliary excretion)

urine

Question 32

Succynilcholine metabolism and elimination

Answer 32

Metabolism: Butyrylcholinesterase (98%-99%)

Elimination:
- Liver: none
- Kidney: <2%

Question 33

Atracurium metabolism, elimination and metabolites particularities

Answer 33

Metabolism: Hofmann elimination and nonspecific ester hydrolysis (60%-90%)

Elimination:
- Liver: None
- Kidney: 10%-40%

Metabolites:
Laudanosine, acrylates, alcohols, and acids; although laudanosine has CNS-stimulating properties, the clinical relevance of this
effect is negligible

Question 34

Cisatracurium metabolism, elimination and metabolites particularities

Answer 34

Metabolism: Hofmann elimination (77%?)

Elimination:
- Kidney: Renal clearance is 16% of total

Metabolites:
Laudanosine and acrylates; ester hydrolysis of the quaternary monoacrylate occurs secondarily; because of the greater potency of cisatracurium, laudanosine quantities produced by Hofmann elimination are 5-10 times lower than in the case of atracurium, thus making this a nonissue in practice

Question 35

Vecuronium metabolism, elimination and metabolites particularities

Answer 35

Metabolism: Liver (30%-40%)

Elimination:
- Liver: 50%-60% ≈60%
- Kidney: 40%-50%

Metabolites:
The 3-OH metabolite accumulates, particularly in renal failure; it has ≈80% the potency of vecuronium and may be responsible for delayed recovery in ICU patients

Question 36

Rocuronium metabolism, elimination and metabolites particularities

Answer 36

Metabolism: None

Elimination:
- Liver: >70%
- Kidney: 10%-25%

Metabolites: None

Question 37

Pancuronium metabolism, elimination and metabolites particularities

Answer 37

Metabolism: Liver (10%-20%)

Elimination:
- Liver: 15%
- Kidney: 85%

Metabolites:
The 3-OH metabolite may accumulate, particularly in renal failure; it is approximately two thirds as potent as the parent compound

Question 38

NMBDs have significant penetration through the bloodbrain barrier, but they don’t interact with neuronal nicotinic and muscarinic cholinergic receptors within the central or peripheral nervous system

T or F

Answer 38

F

While NMBDs have little penetration through the bloodbrain barrier, they may interact with nicotinic and muscarinic cholinergic receptors within the peripheral nervous system, in particular the sympathetic and parasympathetic nervous systems and at the nicotinic receptors of the neuromuscular junction

Question 39

These autonomic responses cause by NMBDs are not reduced by slower injection of the muscle relaxant. If identical to the original dose, subsequent doses will produce a similar response (i.e., no tachyphylaxis will occur). This is not the case, however, when the side effect of histamine release is in question. Cardiovascular responses
secondary to histamine release are decreased by slowing the injection rate, and the response undergoes rapid tachyphylaxis

T or F

Answer 39

T

Question 40

NMBDs associated with histamine release

Answer 40

Mivacurium
Atracurium
Succinylcholine

Question 41

Clinical Cardiovascular Manifestations of NMBDs

Answer 41

• Hypotension:
  The hypotension seen with the use of atracurium and mivacurium results from histamine release
• Tachycardia:
  Pancuronium causes a moderate increase in heart rate and, to a lesser extent, in cardiac output, with little or no change in systemic vascular resistance. Pancuronium-induced tachycardia has been attributed to the following: (1) vagolytic action, probably from inhibition of M2 receptors; and (2) sympathetic stimulation that involves both direct (blockade of neuronal uptake of norepinephrine) and indirect (release of norepinephrine from adrenergic nerve endings) mechanisms.
  The tachycardia seen with benzylisoquinolinium compounds is the result of histamine release.

Dysrhythmias:
Succinylcholine and dTc actually reduce the incidence of epinephrine-induced dysrhythmias.
Possibly because of enhanced atrioventricular conduction, the incidence of dysrhythmias caused by pancuronium appears to increase during halothane anesthesia

Bradycardia:
Several case reports described the occurrence of severe bradycardia and even asystole after vecuronium or atracurium administration. All
these cases were also associated with opioid coadministration

Question 42

The muscarinic (M3) receptors are located postsynaptically on airway smooth muscle. Acetylcholine (ACh) stimulates M3 receptors
to cause …

M2 muscarinic receptors are located presynaptically at the postganglionic parasympathetic nerve endings, and they function …

Answer 42

contraction

in a negative-feedback mechanism to limit the release of ACh

sympathetic

Question 43

Small doses of different nondepolarizing NMBDs administered before succinylcholine toprevent fasciculations have an … effect on the development of subsequent depolarizing block produced by succinylcholine.

Answer 43

antagonistic

• Therefore it is recommended that the dose of succinylcholine be increased after the administration of a defasciculating dose of a nondepolarizing NMBD

Question 44

Inhaled anesthetics effects in the NMBDs

Answer 44

Inhaled anesthetics decrease the required dose of NMBDs, and prolong both the duration of action of the NMBD and recovery from neuromuscular block, depending on the duration of anesthesia, the specific inhaled anesthetic, and the concentration (dose) given

Question 45

The rank order of potentiation of neuromuscular block increase with inhaled anesthetics is …

Answer 45

desflurane > sevoflurane > isoflurane > halothane > nitrous oxide

Question 46

The interaction between volatile anesthetics and NMBDs is one of pharmacodynamics, not pharmacokinetics. The proposed mechanisms behind this interaction include …

Answer 46

(1) a central effect on α motoneurons and interneuronal synapses
(2) inhibition of postsynaptic nAChR, and
(3) augmentation of the antagonist’s affinity at the receptor site.

Question 47

Most antibiotics can cause neuromuscular blockade in the absence of NMBDs. The … primarily inhibit the prejunctional release of acetylcholine and also depress postjunctional nAChR sensitivity to acetylcholine.

The …, in contrast, exhibit postjunctional activity only

The … have not been reported to potentiate neuromuscular blockade

Answer 47

aminoglycoside antibiotics, the polymyxins, and lincomycin and clindamycin

tetracyclines

cephalosporins and penicillins

Question 48

How does temperature affect the NMBDs?

Answer 48

Hypothermia prolongs the duration of action of nondepolarizing
NMBDs

• The force of contraction of the adductor pollicis decreases by 10% to 16% per degree Celsius decrease in muscle temperature lower than 35.2°C. To maintain the muscle temperature at or higher than 35.2°C, the central temperature must be maintained above 36.0°C

Question 49

How does Mg affect the NMBDs?

Answer 49

Magnesium sulfate, given for treatment of preeclampsia and eclamptic toxemia, potentiates the neuromuscular blockade induced by nondepolarizing NMBDs.

The mechanisms underlying the enhancement of nondepolarizing block by magnesium probably involve both prejunctional and postjunctional effects. High magnesium concentrations inhibit Ca2+ channels at the presynaptic nerve terminals that trigger the release of acetylcholine. Further, magnesium ions have an inhibitory effect on postjunctional potentials and cause decreased excitability of muscle fiber membranes

Question 50

How does lithium affect the NMBDs?

Answer 50

By its activation of K+ channels, lithium inhibits neuromuscular transmission presynaptically and muscular contraction postsynaptically. The combination of lithium and pipecuronium results in a synergistic inhibition of neuromuscular transmission, whereas the combination of lithium and succinylcholine results in additive inhibition. Prolongation of neuromuscular blockade was
reported in patients taking lithium carbonate and receiving
both depolarizing and nondepolarizing NMBDs

Question 51

In humans, maturation of neuromuscular transmission occurs …, although immature junctions have been found up to …

Answer 51

after the first 2 months of age

2 years of age

Question 52

Why does the routine administration of succinylcholine to healthy children should be discontinued? I

Answer 52

n apparently healthy children, intractable cardiac arrest with hyperkalemia, rhabdomyolysis, and acidosis may develop after succinylcholine administration, particularly in patients with unsuspected muscular dystrophy of the Duchenne type

Question 53

Particularities of NMBDs use in older patients

Answer 53

In general, when maintaining neuromuscular blockade with nondepolarizing NMBDs in older patients, one can expect that, with the exception of atracurium and cisatracurium, the dosing interval will be increased to maintain the desired depth of neuromuscular blockade. The choice of drug and monitoring the depth of blockade are exceptionally important in this population because recovery of neuromuscular function is generally delayed in older patients

Question 54

Particularities of NMBDs use in obese patients

Answer 54

The level of plasma pseudocholinesterase activity and the volume of extracellular fluid, which are the main determinants of the duration of action of succinylcholine, are increased in obese patients. For complete neuromuscular paralysis and predictable intubating conditions, a 1-mg/kg dose based on total-body weight (TBW) is recommended.

The nondepolarizing NMBDs should be given to obese patients on the basis of IBW rather than on their actual body weight, to ensure that these patients are not receiving relative overdoses and to avoid prolonged recovery.

Question 55

About the NMBDs, only … are independent of renal function.

… elimination is mainly independent of kidney function. However, … is metabolized by plasma cholinesterases, and concentrations may be slightly decreased in patients with severe renal failure

Answer 55

atracurium, cisatracurium, and, to some extent, vecuronium

Succinylcholine

succinylcholine

• The decrease in plasma cholinesterase activity is always moderate (30%) and does not result in prolongation of succinylcholine-induced neuromuscular block

Question 56

How does hepatobiliari disease affect the NMBDs?

Answer 56

Delayed onset of action and an apparent resistance to nondepolarizing muscle relaxants occur in patients with
cirrhosis, although studies demonstrated that the sensitivity
of the neuromuscular junction was unaltered. This is the
consequence of the increased volume of distribution, which
induces greater dilution of muscle relaxants in cirrhotic
patients.
The increase of terminal half-life can be secondary to either the increased volume of distribution or decreased biliary excretion for muscle relaxants dependent on hepatic function for elimination

In patients with severe liver disease, butyrylcholinesterase
activity is decreased because of decreased synthesis of
the hepatic enzymes

Because of the wide interindividual variations seen in the response to nondepolarizing muscle relaxants in patients with hepatic disease, quantitative monitoring of neuromuscular block is required, with careful titration of doses

Question 57

Conditions Associated With Upregulation of Acetylcholine Receptors

Answer 57

Spinal cord injury
Stroke
Burns
Prolonged immobility
Prolonged exposure to neuromuscular
blockers
Multiple sclerosis
Guillain-Barré syndrome

Question 58

Conditions Associated With Downregulation of Acetylcholine Receptors

Answer 58

Myasthenia gravis
Anticholinesterase poisoning
Organophosphate poisoning

Question 59

After a period of immobilization, burn injury causes upregulation of both fetal (α2βγδ) and mature (α2βεδ) nAChRs.328 This upregulation of nAChRs usually is associated with … to nondepolarizing NMBDs and … to succinylcholine

Answer 59

resistance

increased sensitivity

Question 60

The magnitude of the hyperkalemic response appear to correlate closely with the magnitude of the burn injury

T or F

Answer 60

F

The magnitude of the hyperkalemic response does not appear to correlate closely with the magnitude of the burn injury. Potentially lethal hyperkalemia was seen in a patient with only an 8% total BSA burn

Question 61

Succinylcholine has been safely administered within … of a burn injury. It can be used for prehospital or emergency room intubation. After an initial … interval, however, sufficient alteration in muscle response may have occurred

Answer 61

24 hours

24-hour