Neuromuscular blocking drugs Flashcards
Apart from depolarising and non-depolarizing MR, what alternative techniques exist to provide a sufficient degree if muscle relaxation to facilitate intubation and surgery (i.e. in the paediatric population to avoid use of muscle relaxants)
- High dose induction agent OR high dose volatile agent can provide enough muscle relaxation to facilitate intubation and surgery.
- Obviously accompanied by increased side effects. - Peripheral nerve blocks will provide muscle relaxation when they are able to block motor nerves.
- Neuraxial anaesthesia can also provide substantial motor nerve blockade and adequate muscle relaxation.
How do volatile agents act as muscle relaxants
They are calcium channel antagonists
How can indications for neuromuscular blockade be classified?
- Patient factors
- Anaesthetic factors
- Surgical factors
- Intensive care
What are the patient factors that indicate muscle relaxation?
Any patient at risk for gastric contents regurgitation require rapid airway protection of their airway with an endotracheal tube.
Which patients are at risk for regurgitation of gastric contents
FULL STOMACH
- Patients undergoing emergency surgery
- Trauma
- Not fasted
GIT PATHOLOGY
- Gastroparesis (Diabetic or other)
- SBO
- Gastric outlet obstruction
- Esophageal stricture
- GORD
INCREASED INTRA-ABDOMINAL PRESSURE
- Morbid Obesity
- Ascites
PREGNANCY from 16/40 onwards –> RSI
What are the anaesthetic factors that indicate neuromuscular blockade?
- Control of patient ventilation
- respiratory disease
- abnormal position (prone, lateral, deck chair)
- Facilitation of endotracheal and airway devices (ETT and rigid bronchoscopes)
What are the surgical factors that indicate muscle relaxation?
- Microsurgery - any movement or cough would compromise surgical technique: Neurosurgery | ENT |Intra-ocular.
- Laparotomy | Laparoscopy –> prevent iatrogenic bowel injury
- Orthopedics: Assists with mechanics of relocating joints and fixing fractures
- Cardiac and thoracic surgery require paralysis
- Psychiatry: ECT –> ECT –> reduction of motor manifestations.
When is muscle relaxation required in intensive care
No longer used routinely in ICU but in a few instances prolonged ventilation may require neuromuscular blockade (e.g. tetanus)
What should always be done prior to the administration of a muscle relaxant
The airway be assessed and planned for.
What are the 8 P’s for RSI that can be applied to the management of any airway
Plan (DSI/RSI ; Difficult/Not ; LMA/ETT ; Ramping/Not) Preparation (STOP IC BARS, IMALES, Drugs, Theatre) Protect C-Spine (if relevant) Position (flextension) Preoxygenate Paralysis and Induction Placement ETT/LMA Post intubation care
Define the neuromuscular junction
IT is the region where the motor neuron and the muscle cell approximate
What is the distance of the synaptic cleft?
20nm
List the sites at which Ach is the neurotransmitter
- PSNS (entire system)
- SNS
- Sympathetic ganglia
- Adrenal medulla
- Sweat Glands - CNS (some neurons)
- Somatic nerves ending in skeletal muscle
What is the name of the post synaptic terminal within the neuromuscular junction?
Motor end plate - this is the site of Ach receptors
A specialised portion of the muscle membrane
What happens when an action potential arrives at the pre-synaptic terminal
- Influx of Ca ions via V-gated Ca channels
- Ca allows fusion of pre-synaptic Ach vesicles to fuse with the pre-synaptic membrane and exocytose Ach into the synaptic cleft
What happens after the Ach has been released into the synaptic cleft (20nm)
- Diffuse across the 20nm cleft
2. Bind to nicotinic Ach receptors on a specialised portion of the muscle membrane: the motor end plate
How many nicotinic Ach receptors exist within each neuromuscular junction and activation of how many of these receptors is required for normal muscle contraction.
What is the clinical significance of this
5 million Ach receptors per NMJ
Activation of only 500 000 –> normal muscle contraction
Clinical significance - 10 fold safety net is lost in:
- Eaton Lambert myesthenic syndrome (decrease release Ach)
- Myesthenia gravis (decreased receptors)
Describe the structure of the Ach receptor
5 protein subunits that surround a central transmembrane pore
Protein subunits
- two alpha
- epsilon
- delta
- beta
Anticlockwise from 12 oclock: alpha, epsilon, alpha, delta, beta.
Which protein subunits on the receptor can Ach bind and when is the central channel opened
the alpha subunits
The central ion channel will only open when a molecule of Ach is bound to both subunits
Describe the structure and location of the alternative isoform ‘immature’ Ach receptor
Anticlockwise from 12 o’clock: alpha, gamma, alpha, delta, beta
Location:
- Fetal muscle
- In the adult: ‘extrajunctional’ –> it may be located anywhere on the muscle membrane: inside or outside the NMJ.
What happens when the conformational change occurs within the Ach receptor
The central ion channel opens allowing the brief movement of cations:
Na and Ca –> move in
K –> moves out
This generates an end plate potential
Explain how the postjunctional membrane is depolarized
Each Ach vesicle contains a ‘quantum’ (10^4) of Ach molecules. The number quanta released depends on the extracellular Ca concentration (N ± 200 quanta).
When enough nicotinic receptors are occupied by Ach - Voltage gated sodium channels in the perijunctional membrane open and the end plate potential will be sufficiently strong to depolarize the perijunctional membrane.
How is the perijunctional action potential propagated and what is the result of this propagation?
Along the T-tubule system, opening Na channels and releasing Calcium from the sarcoplasmic reticulum –> Increasing intracellular calciumallows contractile proteins actin and myosin to interact, bringing about muscle contraction.
How is Ach removed from the cleft
Acetylcholinesterase hydrolyzes Ach into acetate and choline.
Achase is embedded in the motor end plate membrane immediately adjacent to the Ach receptors. Choline is taken up by the pre-synaptic membrane where it is re-cycled and a=combined with acetyl Co A to form acetylcholine
What happens after Ach unbinds
The ion channel closes. The end plate repolarizes. Calcium is resequestered back in the SR. The muscle cell relaxes.
List three ways that muscles can be relaxed
Block the:
- Nerve: Local anaesthetics and botox
- NMJ: NMBs
- Muscle: Dantrolene (Rx malignant hyperthermia)
Differentiate the mechanism of action of depolarizing and non-depolarizing muscle relaxants
DEPOLARIZING
- 2 Ach molecules bound –> binds to Ach receptor –> depolarization –> occupies the Ach receptor until metabolized by pseudocholinesterase (takes ± 5 mins) (not acetylcholinesterase)
NON-DEPOLARIZING
- Bind Ach receptor - do not cause depolarization - prevent Ach from binding (competitive antagonists)
- In the early stages the bond is very strong and cannot be displaced by increasing Ach (Neostigmine)
List 5 factors that potentiate and prolong the action of muscle relaxants
- Drugs:
- Volatile agents
- Aminoglycosides (gentamicin) - Electrolytes
- Increase Mg
- Decrease Ca
- Increase/Decrease K - Acidosis
- Temperature
- Hypothermia potentiates SUX
- Hyperthermia potentiates non-depolarizers - Myaesthenia gravis and other inherited muscle abnormalities: e.g dystrophies/dystonias
Classify the muscle relaxants (NMJ)
DEPOLARISING (4 - 10 minutes)
- Succinylcholine/Scoline (1 - 1.5 mg/kg)
NON-DEPOLARISING
Short acting (12 - 18 mins)
- Mivacurium (0.15 mg/kg) (not in RSA)
Intermediate acting
- Rocuronium (0.6 - 1.2 mg/kg) High dose for RSI
- Vecuronium (0.1 mg/kg)
- Cisatracurium (0.1 mg/kg) Good for renal/liver failure
- Atracurium (0.5 mg/kg) Good for renal/liver failure
Long acting
- Pancuronium (0.1 mg/kg) (being phased out)
Describe the chemical structure of succinylcholine
Consists of two molecules of acetylcholine liked together by two quaternary amine groups
Describe the presentation of succinylcholine
Glass ampoule stored in the fridge
2ml: 50mg/ml
How long does it take sux to cause flaccid paralysis
30 - 60 seconds (after fasciculations)
How long does flaccid paralysis last after sux
Depends on Age/Dose/Route
IV: 4 - 10 mins
IM: 10 - 30 mins
How long can muscle pain last after sux
up to 3 days
Can be very severe
More common in fit and active individuals
By how much does a single does of sux increase plasma potassium concentration and why does this occur. Which patient’s are at risk from this sudden rise in potassium
0.5 mmol/L. Ubiquitous muscle depolarization and contraction leads to release of K from the muscle into the plasma.
Patient’s at risk:
- Renal failure with K > 5 mmol/L
- Massive tissue injury (burns/crush)
- Disuse of muscle for weeks to months (paraplegia/stroke/end stage disease)
Summarise the adverse effects of succinylcholine
- Fasciculations and muscle pain for 3 days
- Raised IOP, ICP, IGP
- Tachycardia (usually adults 1st dose)
- Bradycardia (children and adults 2nd dose)
- Rise in K by 0.5 mmol/L relevant in
- Renal failure with K > 5.0 mmol/L
- Massive tissue injury: crush/burns
- Prolonged tissue disuse: Stroke/Paraplegia/End stage
- –> dysrhythmias - Trigger of Malignant hyperthermia
Describe the metabolism of succinylcholine and factors that affect the break down of succinylcholine and hence potentiate the action of sux.
Broken down by plasma cholinesterase (also called pseudocholinesterase or butyrylcholinesterase)
–> Synthesised in the liver and present in the plasma
The action of plasma cholinesterase and hence SUX metabolism can be affected by the following factors:
- Hypothermia/Acidosis/Electrolytes/Drugs
- Liver disease
- Pregnancy
- Drug interaction
- Acetylcholinesterase inhibitors (neostigmine)
- Aminoglycosides
- Lithium
- Loop diuretics
What is scoline apnoea and what is the treatment of scoline apnoea
Inherited disorder (homo/heterozygous) - Abnormal pseudocholinesterase --> varying degrees of activity and prolonged paralysis
Treatment:
- Supportive: Sedate, ventilate and wait.
- Administer FFPs –> contains normal plasma cholinesterase
How does succinylcholine bring about muscle relaxation if it depolarizes the motor end plate, perijunctional membrane, T-tubules and the muscle tissue?
Succinylcholine binds to the alpha subunit of the nicotinic Ach receptor BUT is not quickly metabolised by acetylcholinesterase and hence remains bound. Continuous end-plate depolarization causes muscle relaxation because opening of perijunctional sodium channels is TIME limited –> sodium channels rapidly ‘deactivate’ (Two gate theory). The sodium channels cannot reopen until the end plate repolarizes. This is called phase 1 block. After a period of time, prolonged end plate depolarization can cause poorly understood changes in the ACh receptor that result in a phase 2 block, which clinically resembles that of nondepolarizing muscle relaxants
What is phase 2 block
Prolonged motor end plate depolarization leads to poorly understood changes in the ACh receptor that result in a phase 2 block, which clinically resembles that of nondepolarizing muscle relaxants.
How do non-depolarizing muscle relaxants cause muscle relaxation
Competitive antagonists of postsynaptic ACh receptors
- Upon binding the Ach receptor, no conformational change occurs for ion channel opening but Ach is prevented from binding to its receptors. Neuromuscular blockade occurs even if only one alpha subunit is blocked.
Describe how the presence of prolonged muscle disuse would affect the actions of depolarising and non-depolarising muscle relaxants
Chronic disuse –> Upregulation of mature nicotinic Ach receptors within the neuromuscular junction and promoted expression of immature isoform extrajunctional Ach receptors.
For depolarising MR
–> An exaggerated response is observed with compounding of side effects
For non-depolarizing MR
–> Resistance (more receptors must be blocked)
Describe the impact of myasthenia gravis on depolarising and non-depolarising muscle relaxants
Myesthenia gravis is the autoimmune destruction of nicotinic Ach receptors in the neuromuscular junction.
This leads to lower numbers (less expression/down regulation) of these receptors.
This leads to a resistance to depolarizing agents and increased sensitivity to non-depolarizing agents.
Do acetylcholinesterase inhibitors (neostigmine/pyridostigmine) reverse muscle relaxation brought about by succinylcholine?
Phase 1 block
- no reversal
- possible potentiation and prolongation of block by inhibiting pseudocholinesterase
Phase 2 block
- Possibly assists with reversal of a phase 2 block (altered Ach receptors by prolonged depolarization) when TOF fade is present and sufficient time has past for circulating sux to be negligible.
What is suggamadex and how does it work
- Modified gamma-cyclodextrin
- Rapidly encapsulates aminosteroid NDMR (1:1)
- -> this promotes their dissociation from Ach receptors and terminating their action. - Rapid onset
- Reverses profound block without evidence of reversibility
- CVS stable
- Excretion: Renal
- Very expensive - not available in all scenarios
- Used in CICO scenarios
Works for Aminosteroids = Roc | Vec | Pan
Does not work for benylisoquinoliniums (Cis | Atra | Miv)
Does suggamadex reverse Atracurium/Cisatracurium/Mivacurium
No. It does not reverse benzylisoquinoline compounds. It only binds and reverses steroid NDMR (Vecuronium/Rocuronium/Pancuronium)
What is the name of the first NDMR and where does it come from
Curare. South American vine. Used by hunters on the tips of arrows. Chemically curare is a benxylisoquinoline. the muscle relaxants atracurium, cisatracurium and mivacurium are based on this chemical structure
Name the aminosteroid NDMR
Vecuronium
Rocuronium
Pancuronium (no longer in general use due to its long elimination and context-sensitive half time and predominantly renal clearance)
Do NDMR cross the BBB/Placenta
No. They are large, highly ionized, water soluble and have virtually no penetration of lipid barriers such as the placenta and BBB
How long can the following agents be stored outside the refrigerator in theatre (±25 deg C)
Vecuronium
Cisatracurium
Atracurium
Rocuronium
Succinylcholine
Vecuronium - 1 week
Cisatracurium - 3 weeks
Atracurium - 1 month
Rocuronium - 3 months
Succinylcholine - 1 month
VCARS 13131
Describe the presentation of the muscle relaxants
SUX - Liquid. Brown glass. Fridge (2 - 8 deg C). 100mg/2ml
ROC - Clear liquid in clear glass. Fridge. 50mg/5ml
CIS - Clear liquid in clear glass. Fridge. 10mg/5ml
ATRA - Clear liquid in clear glass. Fridge .50mg/5ml
VEC - White Powder. Clear glass. Reconstitute to 2mg/ml.
Which 2 muscle relaxants do not cause histamine release
No Histamine release
CIS
VEC
How are atracurium and cisatracurium metabolized and why is this relevant
Metabolism is via nonspecific esterases occurring at physiological pH and temperature.
Both agents are safe in Liver and Renal disease
VEC and ROC have renal and hepatic metabolism
Summarise the duration of action (time to 25% recovery) of the muscle relaxants
DEPOLARISING
- Succinylcholine/Scoline: 5 - 10 mins
NON-DEPOLARISING
Short acting
- Mivacurium: ± 15 mins
Intermediate acting
- Rocuronium ± 30 mins
- Vecuronium ± 30 mins
- Atracurium ± 30 mins
- Cisatracurium ± 45 mins
Long acting
- Pancuronium ± 90 mins
Historically, why were muscarinic and nicotinic receptors distinguised
Muscarine - poison from the mushroom amanita muscaria - binds muscarinic receptors –> hypercholinergic state: bradycardia and increased secretions.
MUSCARINIC receptors - End organ effector cells --> Heart (SA and AV) --> Smooth Muscle (bronchi and GIT) --> Glands (salivary and lacrimal) BLOCKED by anticholinergics like atropine and glycopyrrolate
Nicotine - Nicotiana tabacum –> binds nicotine receptors
NICOTINIC receptors
- autonomic ganglia
- skeletal muscle
BLOCKED by non-depolarizing muscle relaxants
How long does Acetylcholinesterase usually take to work and why is this relevant to NDMR
Milliseconds
if AChase is inhibited by neostigmine there is significantly more Ach available to compete with the NDMR at the end-plate nicotinic receptors and hence reversal is possible using AChase inhibitors
What are the unwanted PSNS effects that will result from the administration of neostigmine and what is given to prevent this
Bradycardia Bronchospasm Secretions Increased bowel motility Pupillary constriction
Muscarinic blocking agents are given: Atropine or Glycopyrrolate
Where does atropine come from and what does intoxication cause
Plant: Deadly night shade (Belladonna)
Anticholinergic syndrome:
Hot as a hare - no sweating –> heat retained
Red as a beet - no sweating –> VD to try remove heat
Dry as a bone - dried secretions and no sweating
Blind as a bat - pupillary dilatation + ineffective accommodation
Mad as a hatter - CNS muscarinic receptors blocked
What are the doses for the reversal agents
0.2 mg/kg Pyridostigmine (10 - 15 mg)
- 04 mg/kg - Neostigmine (2.5mg)
- 02 mg/kg - Atropine (1 mg)
- 01 mg/kg - Glycopyrrolate (0.4 - 0.6 mg)
How long does it take neostigmine | Glycopyrrolate | Atropine take to work and what is their duration of action
Neostigmine IV
TTPE: 5 mins
Duration: 90 mins
Glycopyrrolate IV
TTPE: 3 mins
Duration: 120 mins hours
Atropine IV
TTPE: 2 mins
Duration: 60 mins
When is it safe to administer the reversal agent and what happens if this is administered too early?
When is it safe to administer reversal
- Clinical signs (unreliable)
- Gag reflex | breathing | coughing | eye opening
- Head lift 5 - 10s | hand squeeze | Jaw grip tongue depressor - Peripheral nerve stimulator
“Evidence of reversibility”
- > 30 minutes since administration of last dose AND 3 or more twitches present
Early reversal leads to residual neuromuscular blockade and postoperative pulmonary complications (POPCs)
What is a “supramaximal stimulus”
Supramaximal stimulation is stimulation having current significantly above that required to activate all the muscle fibers. …
Which nerves can be used for monitoring and why
Ulnar nerve - adductor pollicis brevis
Posterior tibial nerve - ankle plantar flexion
Facial nerve - orbicularis occuli
Common peroneal nerve (neck of fibula)
These are all superficial nerves
What current is usual entered into the PNS and what is the usual duration of each stimulus
Current: 15 - 40 mA
Duration: 2 ms
What are the common types of stimulation used and what is the specific benefit of each
- Twitch (1 Hz every 10 seconds) - immediately after administration MR to ensure patient is paralyzed before intubation
- Train-of-four (TOF) (2 Hz = 4 twitches over 2 seconds)
- Fade present (1st twitch bigger than 4th twitch with NDMR)
- May be less than 4 twitches if PNS used soon after administration NDMR.
- No fade with SUX - all twitches have lower amplitude - Tetany (50 - 100 Hz) used to detect any residual block
- Double-Burst Stimulation (DBS) - two bursts of 50 Hz - easier to see if fade is present when TOF is difficult to distinguish
- Post-tetanic facilitation or potentiation
–> Used to assess more profound degrees of NMB
50 Hz for 5 seconds (5 second tetanus)
then 3 second pause and 20 twitches at 1Hz
The number of contractions visible post tetany will predict the time required before reversal feasible.
List 8 signs of inadequate reversal
A
B - Abnormal breathing x 4
- Tracheal tug
- Jerky respiration
- Poor chest expansion
- Poor ability to cough
C
D - Abnormal Neuro x 4
- Weak hand grip
- Inability to raise head from pillow > 5 s
- Restlessness
- Ptosis
Explain the clinical use of post-tetanic facilitation
It is a method for monitoring intense neuromuscular blockade.
50-Hz tetanic stimulus to the ulnar nerve for 5 s,
3 second break
followed by single twitch stimulation at 1 Hz.
The number of twitches observed in the period of
post-tetanic facilitation, the post-tetanic count,
correlates inversely with the degree of neuromuscular blockade.
Post-tetanic counts of 6-7 indicate that the return of the first TOF twitch is imminent.
What are the physiological implications of residual neuromuscular blockade?
A - Aspiration (impaired cough, impaired phonation), obstruction
B - Aspiration, ventilation, oxygenation
C
D + E: impaired muscle tone and co-ordination
What are the signs and symptoms of residual muscle paralysis
“Fish out of water”
- Difficulty: breathing, speaking, seeing
- Uncoordinated weakness
- Significant patient distress
What are the clinical implications of residual muscle paralysis
Airway - obstruction/aspiration
Breathing - POPC, prolonged ventilator weaning, postoperative hypoxia
How man receptors are blocked with TOFC 0, 1, 2, 3, 4
TOFC 4: 0 - 75% TOFC 3: 75% TOFC 2: 80% TOFC 1: 90% TOFC 0: 100%
Describe how the TOF and PTP is administered including current, frequency, duration
TOF
- Current: Supramaximal > 60 mA
- Frequency: 2 Hz (2 stimuli/second) (each twitch 0.5s)
- Duration: 2 seconds (4 twitches)
PTP
- Current: supramaximal > 60 mA
- Frequency: 50 Hz (50 stimuli/second) for 5 seconds followed by 1 Hz for prn seconds
- Duration: variable - count the 1 Hz twitches and interpret
How is post tetanic stimulation interpreted
Count of 1 twitch post tetany - First TOF twitch should appear in about 30 minutes
Count of 7 twitches post tetany - First TOF twitch should appear imminently
What is the physiology behind the ‘fade’ phenomenon?
Fade may be due to prejunctional effect of non-depolarising muscle relaxants that reduces the amount of Ach in the nerve terminal available for release during stimulation
