Module D-1 Neuromuscular Blockers Flashcards
Mediator in Ach release from Presynaptic
Voltage gated Ca channels
Doubling extra cellular calcium causes 16-fold increase in Ach release
How much Ach is released into Synaptic cleft and why?
At least 200 quanta, 1 quanta= 5000 Ach
Rapid transmission and increased margin of safety
Function of Schwann cell in NMJ
Synapse maturation
Describe events in synaptic cleft
Approximately 50% of ACh is degraded rapidly by acetylcholinesterase or diffuses out of cleft.
Degraded to acetate and choline- this terminates activity
Choline is recycled by Presynaptic terminal
Describe postsynaptic membrane
Highly corrugated with deep invaginations- surface area
“Shoulders” have high concentration of AChReceptors
Voltage gated Na channels are in the folds
Describe postjunctional nicotinic ACh receptor
Pentameric, ligand gated ion channel with 5 subunits
2-alpha, 1-beta, 1-delta, 1-epsilon
Location of the ACh receptor binding site, subunits
At interface of α-δ and α-ε subunits
The end terminus of each subunit creates binding site
Alpha-delta may be most important
Describe ion flow when ACh receptor is agonized
Influx of Na and Ca, efflux of K
This will depolarize the membrane when threshold is reached
Threshold current vs supramaximal current
Lowest current required to depolarize the most sensitive fibers to elicit a detectable response
10-20% higher intensity than is required to depolarize
Describe TOF
Four stimuli every 0.5 sec (2Hz)
TOF ratio
TOFR
Amplitude of the fourth response is divided by the amplitude of the first response
Control should be 1.0
Explain fade
Competition of NMBA and ACh for pre-synaptic NicotinicAChR results in progressively less and less reputake of choline from the synaptic cleft so less acetylcholine is available to be released with each neuron firing
Block of positive feedback loop involving presynaptic receptors and choline
Progressively less twitch
Role of Ca in Presynaptic NMJ terminal
Voltage gated Ca channels open in response to neuronal firing which brings Ca into the Presynaptic terminal and promotes movement of vesicles toward release into NMJ
Double burst stimulation
Two short bursts of 50Hz titanic stimulation separated by 750 ms
Easier to detect fade i.e. recovery from blockade
Tetanus
Rapid electrical stimulus, 50/100Hz
Produces sustained muscle contraction
Succinylcholine’s MOA
Mimics ACh and depolarizes post-synaptic membrane
But it is not hydrolysis by acetylcholinesterase so it has prolonged binding which prevents any further depolarization- resulting in relaxation
What hydrolyzes succinylcholine?
PLASMA cholinesterase
Sux dosing and relationship to potency
ED95 of 0.3-0.6 mg/kg
Intubating dose=1-1.5 mg/kg to achieve intubating conditions within a minute
Speed of onset is inversely related to potency
Sux Duration and clearance
Plasma half-life of 2-4 minutes
Recovery in 13 minutes
Hydrolyzed by plasma cholinesterase (also called pseudo cholinesterase)
Explain why dibucaine number is important
There are over 75 mutations of pseudocholinesterase which result in prolonged blockade
The dibucaine number is used to identify individuals who have an atypical genotype
Explain dibucaine percentages
Dibucaine number is the % of PChE that was inhibited
Dibucaine inhibits normal PChE to a greater degree than atypical PChE
80 (normal)= 80% of PChE activity inhibited
20 (homozygous atypical)= 20% was inhibited
50 (heterozygous atypical)= 50% was inhibited but will likely not display a prolonged block with Sux
Describe differences between ACh Receptors
Nicotinic (NMJ pre and post synapse) NAchR
-ligand gated ion channel (ionotropic)
-Signal skeletal muscle contraction
Muscarinic (mAchR)
-G-protein coupled
-parasympathetic nervous system with diverse functions
Myasthenia Gravis
Disorder of postsynaptic neuromuscular transmission
Caused by antibody-mediated reduction in number of functioning postsynaptic AChRs
Leads to loss of postsynaptic folds and voltage gated Na channels
Characterized by fluctuating fatigable weakness in skeletal muscle
Congenital recessive syndrome
Where are large stores of Ca in the muscle?
Sarcoplasmic reticulum
Ryanodine
Receptor that allows Ca to move out of Sarcoplasmic reticulum and cause muscle contraction
MH is the abnormal release of Ca and muscle contraction….
Sux contraindications
Hyperkalemia-ESRD okay if serum K is up to date and acceptable
Burn patients (variable criteria)- may be safe in first 24hrs
Severe muscle trauma (crush)
Upper motor neuron/ lower motor neuron disease
Severe sepsis
Muscle wasting (disuse atrophy/denervation)
Malignant hyperthermia
Skeletal myopathy (duchenne)
Atypical PChE
H/o anaphylaxis/allergy
Sux Adverse effects
Tachycardia
Bradycardia- severe in repeat dosing (muscarinic ACh receptors)
Increased potassium
Increased ICP/IOP
Masseter muscle spasm
Why do we not give Sux to kids
Emergencies only due to likelihood of undiagnosed duchenne muscular dystrophy
Which can lead to hyperkalemic rhabdomyolysis
Pathological conditions with potential for hyperkalemia with succinylcholine
Upper/lower motor neuron defect
Spinal cord trauma
Prolonged chemical denervation- muscle relaxants, magnesium, clostridia’s toxins
Direct muscle trauma, tumor or inflammation
Select muscular dystrophies
Thermal trauma
Disuse atrophy
Stroke
Tetanus
Severe infection
List the benzlisoquilnolinium compounds
Atracurium
Cisatracurium
Mivacurium
Atracurium
Competitive antagonism or AChR pre and post synapse
Onset up to 3 minutes, duration 30-60 minutes
Hoffman elimination
HISTAMINE RELEASE-tachycardia and hypotension- stimulation of histamine receptors-NO DIRECT action on cardiac muscle
Do muscle relaxants cross the BBB?
NO mother fucker
Water soluble at physiologic pH
Hoffman elimination
Spontaneous, base-catalyzed non-enzymatic chemical reaction that cleaves NMBDs into two molecules
Slowed by hypothermia and acidosis
Cisatracurium
Competitive antagonist
Does not provoke histamine release
IV bolus (2x ED95) 0.1 mg/kg =relaxation within 3 minutes
Intermediate acting and dose dependent-
2xED95= 45 min
4xED95= 68 min
Hoffman elimination, some renal elimination but recovery is not impacted by liver or renal failure
Active metabolite- laudanosine
Mivacurium
Ultra short acting
Not available in US due to severe bronchospasm(histamine release)
-pseudocholinesterase?
Short duration of action but long onset time makes intubating conditions transient
List steroidal NMBDs
Pancuronium
Vecuroium
Rocuronium
Pancuronium
Not recommended due to long duration of action of 60-90 minutes
Onset~4minutes
Renal excretion and should not be used in renal dysfunction
Also hepatic elimination in the bile-should be avoided in cirrhosis
Vecuronium
Intermediate acting- 36 min after 0.1 mg/kg
ED95 0.05 mg/kg
At 2xED95 (0.1) onset is 3 min
Elimination halftime is 51-90 min-hepatic clearance
Avoid continuous admin due to metabolite with 50% potency
Decrease dosing in elderly
Rocuronium
Faster onset than Vec and also intermediate duration
Onset 45-90 seconds 0.6-1.2 mg/kg (2-4xED95)
Drug of choice for RSI if sux is contraindicated
Elimination half-life of 60-120 min
Hepatobiliary excretion with 33% renal
If re-dosing is required consider changing to Cisatracurium as to not depend on renal clearance
Hypothermia and NMBDs
Prolonged block
Decreased efficacy with reversals
Critical to maintain euthermia during perioperative period
Most commonly implicated drugs in an anaphylaxis situation when giving a “routine” anesthetic (9-13) drugs
Rocuronium and succinylcholine
Why do we not stimulate the muscle for TOF?
We want to stimulate the Presynaptic terminal to depolarize to evaluate the NMJ, directly stimulating muscle is postsynaptic and misleading
Describe potency and onset
With low potency agents we need to used more of it, its a numbers game at the NMJ-if we flood it with more drug the onset time will decrease
Why do we use NMBD?
Improve intubating conditions
Mitigate vocal cord injuries/ voice hoarseness
Improve operating conditions
Mechanical ventilation
Effective Dose NMBD
Dose required to produce effect
ED50: 50% reduction in twitch height
ED95: 95% reduction in twitch height
What slows Hoffman elimination?
Hypothermia and acidosis
Metabolite of Atracurium and Cisatracurium
Laudanosine: crosses BBB, causes seizures
Only concern if long term infusion
Best place to measure onset of blockade (intubating conditions)
Muscle= orbicularis oculi (closes eyelid) or corrugator supercilii (eyebrow twitch)
Nerve= facial nerve
Best place to measure recovery of blockade (return of upper airway function)
Muscle= adductor pollicis (thumb adduction) or flexor hallucis (big toe flexion)
Nerve= ulnar nerve or posterior tibial nerve
Mechanism of bradycardia w/ succinylcholine
Stimulation of M2 receptor in SA node
Treating hyperkalemia- K shift and elimination
Calcium-stabilize myocardium
Glucose + insulin
Sodium bicarbonate
Hyperventilation
Albuterol
Lasix
Volume resuscitation
HD
Hemofiltration
Ion flow through Post synaptic AchR
Calcium and sodium influx
Potassium efflux
Why does Sux cause increase in ICP?
Transient effect
Venous congestion due to fasciculation of neck muscles and increased cbf
Offset with ND NMDA or. IV induction agents
Why is sux prolonged in liver failure?
Pseudocholinesterase is produced in the Liver- typically not a significant consideration
Impairment in what organ can prolong sux duration
Liver
It produces pche
Opiates that act differently?!?
Tramadol-norepinephrine and serotonin reuptake blocker
Methadone- NMDA receptor antagonism
What do you do with nmbd dosing if your patient is on anticonvulsants?
Give more!!
