PHARMACOLOGY | NMB Agents Flashcards
Which subunit of the nAchR is present in receptors located at the endplate NMJ but NOT in extrajunctional receptors?
A. β
B. γ
C. δ
D. ε
D. ε
nAchRs found on skeleton muscle are 5-subunit ligand-gated ion channels, consisting of 2 α subunits and 1 each of β, ε (or γ), and δ. ε subunit is found on mature receptors, which are normally located only in the NMJ (aka at the muscle endplate).
With decreased stimulation from the neurons and muscle disuse, such as during periods of immobilization or with muscular dystrophy, stroke, or severe
burn, immature, extra-junctional receptors develop, characterized by the substitution of γ for ε subunits.
During induction of anesthesia for cesarean delivery in a 22-year-old female,
rocuronium is inadvertently substituted for succinylcholine. The neonate does not
show any sign of muscle relaxation because rocuronium is:
A. Highly protein bound
B. “Unaffected by ion trapping”
C. Lipid soluble
D. Highly ionized
D. Highly ionized
Neuromuscular-blocking drugs (NMBDs) are highly charged molecules because of the presence of a quaternary ammonium group in their structure. This makes them poorly lipid soluble so that they do not cross biologic membranes like blood–brain
barrier, renal tubular epithelium, and placenta.
Administration of these drugs thus does not produce central nervous system effects; renal tubular reabsorption is minimal, and maternal administration does not adversely affect the fetus. Issue of ion trapping can only develop if a drug gets trapped in the acidic environment of fetal blood after it has crossed the placenta.
The effect of Ach at the neuromuscular junction (NMJ) is terminated by which
of the following mechanisms?
A. Break down by acetylcholinesterase
B. Break down by pseudocholinesterase
C. Degradation by tissue esterase
D. Reuptake into the nerve terminal
A. Break down by acetylcholinesterase
After depolarization of the motor nerve and a rise in intracellular Ca+2 at the nerve
terminal, vesicles containing Ach are released into the synaptic cleft. Binding of
Ach to nAchRs on muscle cells induces muscle contraction. Ach is then rapidly
hydrolyzed by acetylcholinesterase into choline and acetic acid in the synaptic cleft
as well as at the basement membrane. Choline is subsequently reabsorbed at the
presynaptic nerve terminal.
Pseudocholinesterase is an enzyme responsible for the degradation of
succinylcholine, mivacurium, as well as ester local anesthetics. Similarly, tissue
esterases are responsible for the degradation of other pharmacologic agents, such as remifentanil and atracurium.
Neither of these enzymes plays a role in the
degradation of Ach, resulting in termination of its action at the NMJ.
What is the role of Ca++ in muscle contraction?
Ca+2 binds to and induces a conformational change in troponin which leads to formation of actin-myosin cross-bridge.
Depolarization of the skeletal muscle –> release of Ca+2 from the sarcoplasmic reticulum as well as entry of extracellular Ca+2 –> Ca+2 binds to and
induces a conformational change in troponin –> formation of actin-myosin cross-bridge –> activation of the myosin motor –> thereby producing mechanical contraction.
This NMB agent has an active metabolite almost as potent as its parent drug and accumulates in renal failure:
VECURONIUM
TRUE or FALSE
Onset is faster for the less potent NMB agent.
TRUE
Succinylcholine and rocuronium is less potent compared to Cis-atracurium and Vecuronium, hence they have FASTER ONSET.
Which of the following NMB causes precipitates when given concurrently with Thiopental?
A. Vecuronium
B. Rocuronium
C. Cis-atracurium
D. Mivacurium
A. Vecuronium
Vecuronium is a quaternary aminosteroid with only one metabolite, 3-
desacetylvecuronium. It precipitates out of solution if administered concurrently
with thiopental.
- devoid of vagolytic effects and
histamine release!
IOP increase after a single dose succinylcholine?
up to 15mmHg (ONLY lasts 5 minutes)
Normal intraocular pressure is
12 to 20 mmHg with a diurnal variation of 2 to 3 mmHg, whereas changes in position may induce increases of up to 6 mmHg.
Intraocular pressure increases up to 15 mmHg transiently (5 minutes duration) after administration of succinylcholine
Which of the following has vagolytic property thus causing tachycardia?
A. Mivacurium
B. Cis-atracurium
C. Atracurium
D. Pancuronium
D. Pancuronium
Pancuronium produces tachycardia through a vagolytic mechanism, as well as by direct sympathomimetic actions.
The intubating dose of NonDepo NMB should be 2x ED95?
TRUE
Larger intubating dose SPEEDS the onset and LENGTHENS the duration
Clinical vignette:
While doing a PACU rounds, you noticed that a patient is desaturating to an O2 sat of 70-80%. Upon thorough assessment, your clinical judgement is to secure the airway using RSI technique. However, the patient underwent GA-GETA and neostigmine was used as reversal agent from his previous surgery an hour ago.
What muscle relaxant are you going to use this time and why?
ROCURONIUM 1.2mg/kg
Neostigmine, but not edrophonium, inhibits pseudocholinesterase (in addition to acetylcholinesterase) which leads to a prolonged effect of succinylcholine. Therefore, it is not recommended to administer succinylcholine in cases where surgical muscle relaxation is required
immediately after neostigmine has been administered.
Reference: Barash 9th edit | pp 1613
A patient on succinylcholine infusion has a TOF ratio of 0.3. What does this tell about the patient’s degree of paralysis?
A. Patient is in phase I block.
B. Patient is in phase II block.
C. Patient is recovering from block.
D. Cannot tell from given information.
B. Patient is in phase II block
Phase I, or accommodation, block is characterized by a uniform decrease in the
amplitude of twitches compared with baseline. There is no fade with TOF on phase I block, and adequate recovery will demonstrate return of all 4 twitches. Phase II block is characterized by fade on TOF, tetanic fade, and post-tetanus potentiation.
Which mechanism best explains the fasciculations often seen preceding a phase
I block by succinylcholine?
A. Activation of presynaptic nAchR
B. Activation of postsynaptic nAchR
C. Prolonged muscle depolarization
D. Prolonged muscle repolarization
A. Activation of presynaptic nAchR
Binding of succinylcholine to presynaptic nAchR activates those receptors, stimulating repetitive firing and Ach release from the motor nerve terminal, which are manifested as fasciculations. Succinylcholine competes with Ach for binding to the postsynaptic nAchR and is not metabolized by the acetylcholinesterase present at
the synaptic cleft, producing prolonged activation of the nAchR and muscle
depolarization.
As the depolarized muscle membrane locks voltage-gated sodium channels in the inactivated confirmation, junctional neurotransmission is blocked and flaccid paralysis ensues. This is called a phase I, or accommodation, block.
This block is terminated by unbinding and diffusion of succinylcholine away from
the NMJ back into the plasma and subsequent hydrolysis by plasma cholinesterases. Fasciculations can produce myalgia, and pretreatment with a small dose of nondepolarizing NMBs or NSAIDs has been shown to be effective for myalgia
prophylaxis.
The four most common neuromuscular blocking drugs currently used in clinical practice have an ED95 of either 0.3 or 0.05!
.
TRUE
ED95 for SUX and ROC is 0.3
ED95 for CIS and VEC is 0.05
- There is a highly significant variation between patients in response to all neuromuscular blocking drugs
Nondepolarizing neuromuscular blocking drugs bind and inhibit:
presynaptic α3β2 acetylcholine receptors
BIND - -> INHIBIT - -> MUSCLE RELAX!
Glycopyrrolate has onset and offset times similar to neostigmine.
TRUE
For these reasons, glycopyrrolate is preferred with neostigmine (dose one-fifth
that of neostigmine, 0.2-mg glycopyrrolate for every 1-mg neostigmine)
Intubating dose of ATRACURIUM:
0.5 mg/kg
twice the ED95!
For all neuromuscular blockers the usual intubating dose is 2× or 3× the ED95
TRUE
Which of the following statements provides the most accurate explanation
behind the “faster onset” of rocuronium as compared with cisatracurium?
A. Rocuronium is less potent
B. Rocuronium is more potent
C. Rocuronium is ultrashort acting
D. Rocuronium is long acting
**A. Rocuronium is less potent
The rate of onset of nondepolarizing NMBs generally depends on their potency.
Less potent agents, such as rocuronium (ED95 0.3 mg/kg), have a faster onset of
action as compared with more potent agents, such as cisatracurium (ED95 0.05 mg/kg). Rocuronium and cisatracurium are both intermediate-acting NMBs and
have a duration of action of approximately 30-50 minutes.
**LESS POTENT, FAST ONSET **
Psuedocholinesterase activity is increased in which of the following conditions?
A. Pregnancy
B. Liver failure
C. Obesity
D. Malignancy
C. Obesity
Pseudocholinesterase degrades succinylcholine (SCh), mivacurium, and certain local anesthetics. Intrinsic levels can be affected by certain physiologic and
pharmacologic factors, such as alcoholism or obesity, which both increase butyrylcholine (aka pseudocholinesterase) levels. Butyrylcholinesterase levels may
decrease to 75% of normal during pregnancy and to 67% of normal during
immediate postpartum period; this degree of decrease is not usually clinically
significant, but occasional prolonged apnea from SCh administration may result.
Similarly, significant decrease of synthetic liver function may also result in
prolonged apnea. In addition, plasma butyrylcholinesterase may be inhibited by
exogenous compounds, such as organophosphates (eg, insecticides, chemical warfare agents, and echothiophate, a topical glaucoma agent), anticholinesterase agents (eg, neostigmine, pyridostigmine, and edrophonium), and monoamine oxidase inhibitors (MAOIs).
Conditions with nAChR Upregulation:
SENSITIVE to succinylcholine
RESISITANT to NMBA
According to BARASH, the high-dose of ROCURONIUM is:
0.9 to 1.2 mg/kg
What is ED 95?
The average dose to ACHIEVE 95% suppression of twitch height in 50% of population.
A “defasciculating” dose of a nondepolarizing neuromuscular blocking drug:
5 - 10% of ED95
Which muscle relaxant undergoes biliary excretion?
A. Vecuronium
B. Pancuronium
C. Rocuronium
D. Succinylcholine
E. Both A and C
A. Both A and C
Nondepolarizing neuromuscular blocking drugs are:
Ionized
Hydrophilic compounds
Quaternary ammonium - exhibit limited lipid solubility
CANNOT CROSS BBB and PLACENTA
Only when the residual neuromuscular block is minimal (e.g., train-of-four count of 4 without fade or train-of-four ratio ≥0.4) is neostigmine a highly effective reversal agent.
TRUE
NEO is 0.4! dial 0.4 to get in!!!
Which of the following structures of the skeletal muscle does not change in
length as the muscle contracts?
A. A band
B. I band
C. H zone
D. Z line
A. A band
Skeletal muscle myofibril is composed of densely organized actin (thin) and myosin
(thick) filaments. Histologically, A band contains overlapping actin and myosin,
whereas I band contains actin only.
The distance between 2 Z lines is defined as a sarcomere. When muscle cell is depolarized, rising intracellular Ca+2 leads to formation of actin-myosin cross-bridges in the A band and myosin motor activation
pulls the actin filaments closer together.
Thus, the spaces occupied by I band, H
zone, and between the Z lines become shorter. The A band width remains
unchanged.
Following an intubating dose of a nondepolarizing drug, and once a clinical neuromuscular block is established, about 50% to 75% of the intubating dose is required to reestablish a deeper block.
**FALSE **
Following an intubating dose of a nondepolarizing drug, and once a clinical neuromuscular block is established, only 10% to 25% of the intubating dose is required to reestablish a deeper block (i.e., 0.05 to 0.15 mg/kg for rocuronium).
SEQUENCE of NEUROMUSCULAR TRANSMISSION
Action potential depolarizes –> Ca++ INFLUX –> Fusions in Vesicles –> RELEASE of Ach –> Ach DIFFUSES across synaptic cleft –> binds ALPHA(not beta) subunit of NICOTINIC receptors
When Ach binds both ALPHA –> receptor ION channel OPENS:
Na+Ca++ pasok
K+ alalabas
The lowest train-of-four count for depth of block is called “shallow,”
TOF count: ____
TOF ratio: ____
TOF count - 4
TOF ratio - < 0.4
incidence of anaphylaxis with the use of SUCCINYLCHOLINE:
1:10,000
VERY COMMON!
High yield tip: AGENTS implicated in ALLERGIC REACTION during GENERAL ANESTHESIA
Muscle relaxant is the most common culprit of allergic reaction intraoperatively.
After intubating a 20 y.old ASA I patient, you noticed that the value of your TOF count is 0 and PTC(post-tetanic count) >1. Qualitatively, this is considered as:
A. Deep blockade
B. Complete blockade
C. Moderate blockade
D. Shallow blockade
A. Deep blockade
PTC 0 Complete blockade
PTC >1 Deep blockade
