Week 4: NMBAs Flashcards
Neuromuscular junction consists of (3):
Prejunctional motor nerve ending
Synaptic cleft (contains acetylcholinesterase (AChAse))
Highly folded Postjunctional muscle fiber
In nerve stimulation: depolarization reaches nerve terminal and voltage gated __________ channels open and _________ enters the nerve terminal
Calcium; calcium
In nerve stimulation: storage quanta Vesicles (presynaptic) release ____________ into the cleft
acetylcholine (ACh)
In nerve stimulation: ACh diffuses across the synaptic cleft and binds to the ________________ receptor at the postsynaptic end plate and start of muscle contraction
nicotinic cholinergic
The release of ACh quanta is antagonized by _________ and _________.
Hypocalcemia ; Hypermagnesimia
1 ACh quanta contains __________ to ___________ ACh molecules.
5,000 to 10,000
Post-junctional receptors have ______ subunits.
5
Postjunctional receptors with 2 alpha, 1 beta, 1 delta, and 1 epsilon (Fetal or “Adult”)?
Adult
** mature - after birth
Postjunctional receptors with 2 alpha, 1 beta, 1 delta, and 1 gamma (Fetal or “Adult”)?
Fetal
**immature/fetal-isommer
The two ___ subunits of the receptor contain the ACh-binding sites
a ( the a-recognition site )
If both “a” subunits are occupied then a ________ change happens and a _______ channel opens
conformational ; central
Sodium (and Calcium) move _________ the cell and Potassium moves __________ the cell. Action potential occurs and a muscle contraction happens.
in to ; out of
When a nerve impulse arrives at the neuromuscular junction (NMJ), voltage-gated ion channels open, leading to an influx of __________ within the terminal that causes several hundred vesicles of acetylcholine to fuse with the nerve membrane.
Calcium
The acetylcholine within the vesicles is released into the synaptic cleft, combining with and activating _______________ receptors on the motor endplate, the activation of which opens ion channels on the muscle membrane and depolarizes the membrane.
nicotinic
The release of ________ from intracellular stores stimulates an interaction between actin and myosin, resulting in muscle contraction.
Calcium
Increased Extrajunctional Receptors is called:
Upregulation
Upregulation occurs when?
When frequency of stimulation of NMJ decreases over days or longer.
What could decrease the frequency of stimulation of NMJ? (6)
- Prolonged use of NMBAs in ICU
- Immobilization
- Severe burns
- CVAs (stroke)
- Infection
- Sepsis
In up-regulation, the number of ___________ nAChRs increases
immature
In upregulation: The number of immature nAChRs will have increased sensitivity to _______ and _______ and decreased sensitivity to ___________.
ACh and SCh ; nondepolarizers
The channel opening time of the immature nAChRs is up to 10-fold longer than that of mature receptors and may allow systemic release of lethal doses of intracellular _______ in response to administration of _________.
K+ (Potassium) ; Succinylcholine (SCh)
When does Downregulation of mature nAChRs occur? give example.
During periods of sustained agonist stimulation.
Chronic neostigmine use.
In what condition is neogtigmine chronically used?
Myasthenia gravis
Sustained agonist stimulation leads to __________ to SCh but __________ sensitivity to nondepolarizing NMBAs.
Resistance; extreme .
Uses of muscle relaxants (4):
- Optimize surgical conditions
- Prevent unwanted movement
- Facilitate tracheal intubation
- Improve mechanical ventilation
Primary purpose of muscle relaxants:
Primary purpose is to achieve adequate relaxation of the upper airway, vocal cords, and diaphragm to facilitate intubation and surgery
Neuromuscular blocking agents (NMBA) are NOT ________ and DO NOT cause _______.
anesthetics ; amnesia.
NMBA do not cause awareness; not enough _________ causes awareness
anesthesia
T/F: Complete paralysis is not required for all surgical cases.
True :)
Other ways to produce muscle relaxation besides NMBAs?
- Inhalational agents: iso, sevo, des
- Blocks : regional, spinal
Main site of action of NMBA is on the ________________ receptor at the ________ of the muscle.
nicotinic cholinergic ; endplate
median dose that corresponds to 50% twitch reduction
ED50
corresponds to 95% block (useful relaxation when twitch abolished)
ED95
Characteristics of Neuromuscular Blockers(NMB)
- potency
- onset of action
- duration of action
- recovery index
- intubating condition
relationship between twitch depression and dose
potency
time to maximal blockade
Onset of Action
Time of injection to return of 25% twitch height
( Dose dependent )
Duration of Action
Time interval between 25% and 75% twitch height
( Speed of recovery )
Recovery Index
Two types of Neuromuscular Blocking Agents:
Depolarizing & Nondepolarizing
Depolarize at postsynaptic nAChRs
Depolarizing NMBAs
Example of depolarizing NMBA:
Succinylcholine
Compete for active binding sites on nAChRs
Nondepolarizing NMBAs
Two types of nondepolarizing NMBAs
Aminosteroid & Benzylisoquinolinium
Aminosteroid - Nondepolarizing NMBAs:
Pancuronium
Rocuronium
Vecuronium
Benzylisoquinolinium - Nondepolarizing NMBAs:
- Mivacurium
- Atracurium
- Cisatracurium
made up of two ACh molecules joined end to end; acts as a “false transmitter,” mimicking ACh.
Succinylcholine
Succinylcholine(SCh) (__________)
Anectine
_____________ agent creates an overwhelming persistent stimulation to nAChRs.
Depolarizing agent
with ___________ agents membranes become exhausted and unresponsive to ACh. Muscle contraction cannot recur until return of __________ state.
depolarizing ; resting
Which drug activates the prejunctional receptors to release ACh and it also mimics ACh.
Succinylcholine (SCh) - (Anectine)
Succinylcholine (Anectine) produces sustained depolarization of the __________ membrane and __________ receptors.
Postjunctional; extrajunctional
Succinylcholine causes prolonged depolarization of the motor end-plate which inactivates ________ channels and increases influx of ________.
Na; Sodium
*** exist of potassium from cell
Succinylcholine(SCh)/Anectine was introduced in what year?
1949
How does SCh mimic ACh?
it has Two ACh molecules joined end to end
When given may cause fasciculations before total paralysis, specially in patients with a lot of muscle.
Succinylcholine(SCh)/Anectine
Succinylcholine IV dose
1 -1.5 mg/kg IV
Succinylcholine IM dose in children.
4 -5 mg/kg IM
Why give IM succinylcholine?
Good for laryngospasm
Succinylcholine IV dose in kids.
1.5-2 mg/kg
**children are more resistant.
Succinylcholine IV dose in infants.
up to 3 mg/kg
Infants need an increased amount of SCh becaue
Not enough muscle and larger volume of distribution.
Onset of Succinylcholine(SCh)/Anectine
~ 1 minute ( 30 - 60 seconds).
Duration of Succinylcholine(SCh)/Anectine
5-15 minutes (dose dependent)
Infants need an increased amount of SCh becaue
Not enough muscle and larger volume of distribution.
Hydrolysis of SCh by ______________ occurs in the plasma, where almost ______% of the IV dose of SCh is hydrolyzed before reaching the NMJ,
Butyrylcholinesterase ( AKA Pseudocholinesterase or plasma cholinesterase) ;
90%
Succinylcholine(SCh)/Anectine is broken down by butyrylcholinestarese to :
- Choline
- Succinylmonocholine
Only _____% of SCh administered reaches the NMJ
10%
Recovery occurs when SCh _______ away from the NMJ
Diffuses
Butyrylcholinesterase is synthesize in the _________ and found in the __________
Liver ; Plasma
Factors that lower Butyrylcholinesterase:
Burns
Oral contraceptives
Anticholinesterase
Severe liver disease
Reglan
Advanced age
Malnutrition
Pregnancy
Neostigmine (lesser extent edrophonium) profoundly decreases the pseudocholinesterase activity (at 30 min after administration only 50% normal activity) which means it:
Prolongs SCh block.
Abnormal genetic variant of butyrylcholinesterase (over 20 mutations in the coding of the plasma cholinesterase gene) can cause prolonged muscle relaxation after __________ and _____________.
succinylcholine and mivacurium
Probably won’t know you have the gene until it happens.
Abnormal Plasma Cholinesterase
One way to test for it is to check for Abnormal Plasma Cholinesterase
“Dibucaine number”
Dibucaine number
The percentage of pseudocholinesterase enzyme activity that is inhibited by Dibucaine
Dibucaine number reflects __________ of cholinesterase enzyme (ability to hydrolyze SCh) not the ___________ that is circulating in plasma
quality ; NOT quantity
Types of Butyrylcholinesterase
Homozygous Typical
Heterozygous Atypical
Homozygous Atypical
Butyrylcholinesterase: Homozygous Typical
Dibucaine Number
Response to SCh
D#: 70- 80
R: Normal
Butyrylcholinesterase: Heterozygous Atypical
Dibucaine Number
Response to SCh
D#: 50-60
R: lengthened 50-100%
Butyrylcholinesterase: Homozygous Atypical
Dibucaine Number
Response to SCh
D#: 20- 30
R: Prolonged to 4-8 hrs
It is an agonist at the nicotinic receptor of the NMJ and binds with a high affinity, preventing membrane repolarization and thus subsequent action potentials.
Succinylcholine Block
(Phase I Block)
With continued dosing of a depolarizing NMBA, a type I block can develop into a:
Type II block / nondepolarizing
Cardiovascular Side Effects of SCh
Sinus Bradycardia
Junctional Rhythm
Premature ventricular escapes
ASYSTOLE
** treat with atropine
Cardiovascular Side Effects of SCh are more common with
redosing and in children ;
** a second dose given within 5 minutes of the first
Cardiovascular side effects reflect the actions of succinylcholine at cardiac ______________ receptors where the drug mimics the physiologic effects of acetylcholine.
muscarinic cholinergic
can occur to 80-90 % of patients if not pretreated with nondepolarizer or NSAID before giving SCh.
Faciculations
- Disorganized muscle contractions
In patients given SCh, what is very common 1-2 days postoperatively and can occur in 50-60% of the patients, probably due to fasciculations.
Myalgias
** usually big skeletal muscles
SCh administration associated with elevation in the plasma level of potassium of ______mEq/L in healthy patients
0.5
Severe hyperkalemia after SCh administration in patients with (4):
- Burns
- Severe abdominal Infections
- Severe metabolic acidosis
- Conditions associated with UPREGULATION of extrajunctional AChR.
Conditions associated with UPREGULATION of extrajunctional AChR.
Guillian-Barre syndrome
Hemiplegia
Muscular dystrophies
Burns
Paraplegia
“Guillian & Hemi Must Buy Pasta”
Because of the risk of massive ________, _________ , and ________ in children with undiagnosed muscle disease, succinylcholine is not recommended for use in children except for emergency tracheal intubation
rhabdomyolysis ; hyperkalemia;
death
Patients can develop myoglobinuria from muscle damage after ___________ administration.
SCh.
** most of the patients with rhabdomyolysis and myoglobinuria were subsequently found to have malignant hyperthermia or muscular dystrophy.
increase in tone of the masseter muscle may be an early indicator of ___________ (especially in children)
malignant hyperthermia
It is suggested that the high incidence of masseter spasm in children given succinylcholine may be due to _________ succinylcholine dosage
inadequate;
** probably not enough to cause muscle relaxation
Succynylcholine can ________ intragastic pressure and lower esophageal tone (LES).
Increase
**maybe dpends on the intensity of fasciculations, pre-dose of NDMR.
Succynylcholine can ________ intraocular pressure.
Peak time:
And return time:
Increase
** Peaks at 2-4 min after administration and returns to normal by 6 min
The use of succinylcholine is not widely accepted in open eye injury meaning:
when the anterior chamber is open.
SCh can causes __________ in intracranial pressure.
Increase
SCh side effects: (12)
Sinus Bradycardia
Junctional arrest
Premature ventricular escapes
ASYSTOLE
Fasciculations
Myalgias
Hyperkalemia
Myoglobinuria
Masseter spasm
Increase intragastric pressure and lower esophageal tone (LES).
increased intraocular pressure.
Increased intracranial pressure.
Defasciculating Doses used to be called
Curare Dart
A defasciculating dose of ___________ muscle relaxant administered prior succinylcholine decrease its side effects (Including fasciculations and postoperative myalgias).
non-depolarizing
Order of meds in a rapid sequence when giving Defasciculating dose:
- defasciculating dose.
- sedation (ex. propofol)
- Succynylcholine
__________ after a defasciculating dose
Premature muscle weakness
_____________ acts to block ACh receptor sites in an overwhelming, competitive manner.
Non-depolarizing
Two classes of ND-NMBA
- aminosteroids
- Benzylisoquinolinium
Aminosteroids NMDRs
Pancuronium
Pipercuronium
Vecuronium
Rocuronium
Benzylisoquinoliium NMDRs
Mivacurium
Atracurium
Cisatracurium
Competitively antagonize the presynaptic receptors to decrease release of Ach (fade on TO4)
Nondepolarizing Muscle Relaxants
Nondepolarizing Muscle Relaxants compete with ACh for binding on __________ of the alpha subunits of the nAChRs.
one or both
NDMR are classified according to:
How fast they act:
- long, intermediate, short.
&
Their durationt:
- depending on metabolism, redistribution, elimination and dose given .
Nondepolarizing Muscle Relaxants are almost always given ________
Intravenously.
Rocuronium (_________)
Zemuron
Rocuronium (Zemuron) ___________ action
intermediate
Rocuronium (Zemuron) has RARE histamine release (T/F)?
True :)
*could still cause it but RARE!
Rocuronium (Zemuron) has _______ effect of BP and HR
NO effect.
