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Neuromuscular Blockers (NMBs)
- drugs that block neural transmission at the neuromuscular junction causing relaxation of affected skeletal (NOT smooth) muscles → resulting in paralysis
- also affect the respiratory system
- all are structurally related to Ach & all useful NMBs contain one or two quaternary nitrogens
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Acetylcholine (ACh)
- the neurotransmitter responsible for physiologic transmission of nerve impulses from
- 1. pre- & post-ganglionic neurons of the cholinergic (parasympathetic) nervous system
- 2. pre-ganglionic adrenergic (sympathetic) neurons
- 3. multiple nerve endings in the central nervous system
- 4. neuromuscular junction in skeletal muscles
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What are two types of ACh receptors?
- 1. nicotinic (nAChR)
- 2. muscarinic (mAChR)
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Muscle Activation
1) motor neuron depolarization causes an action potential to travel down never fiber to the neuromuscular junction
- 2) axon terminal depolarization causes an influx of Ca2+
- 3) this triggers fusion of the synaptic vesicles & release of ACh from terminal button
4) ACh diffuses across the synaptic cleft of the NMJ & binds to post-synaptic nAChR located on the muscle fiber at the motor end-plate
{nAChR are pentamers in which two ACh must bind in a specific confirmation to produce agonistic action}
5) binding of 2 ACh molecules to nAChR opens the channels causing an influx of Na+
6) depolarization of the sarcolemma that travels down the t-tubules ultimately causes the release of Ca2+ from the sarcoplasmic reticulum
7) this causes muscle contraction
8) unbound ACh in the synaptic cleft defuses away or is hydrolyzed (inactivated) by acetylcholinesterase (AChase)
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What effect does ACh have on pre-synaptic NMJ nicotinic receptors?
ACh acts on pre-junctional nicotinic receptors in a positive feedback manner to INCREASE its own release during high-frequency stimulation
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What are the two classes of Neuromuscular Blockers?
- 1. Non-Depolarizing NMBs - Competitive
- 2. Depolarizing NMBs
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Non-Depolarizing (Competitive) NMBs
- drugs that competitively antagonize the action of ACh at post-synaptic nicotinic AChRs (found on motor end-plates)
- if ACh isn't able to bind & cause muscle contraction, paralysis is the result
- they reduce the frequency of channel-opening events but once a channel has been opened, they can't affect the magnitude, conductance, or duration of said event
- only 1 NMB molecule is needed to block the nAChR
- usually takes ≥70% blockade of nAChRs to see a paralytic response
- b/c they're competitive blockers their effect is reversible
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What effect do non-depolarizing NMBs have on ACh's binding to pre-synaptic NMJ nicotinic receptors?
- non-depolarizing NMBs BLOCK pre-junctional receptors, meaning ACh cannot bind to them & induce its own release during high-frequency stimulation → ACh fails to mobilize
- this manifests as “Fade Phenomenon”
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Fade Phenomenon
- there is a reduction in twitch height with successive stimuli
- “Fade” constitutes a key property of NON-depolarizing NMBs & is useful for monitoring purposes
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How are NMB blockades monitored?
- non-depolarizing NMBs can be monitored by transdermal stimulation (depolarizing NMBs can't)
- monitoring aims to decrease unwanted effects of NMBs that can come about because of prolonged paralysis or delayed recovery
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Train-of-four (TOF)
- a supramaximal stimulus is delivered by peripheral nerve stimulation & the number of contractions are observed at the nerve being stimulated
- most commonly used technique for monitoring NMBs
- delivered as a group of 0.2 millisecond pulses, spaced 500 milliseconds apart at a frequency of 2 Hz
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What are the two types of Non-Depolarizing NMBs?
- 1) Aminosteroid Derivatives
- 2) Benzylisoquinoline Derivatives
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Aminosteroid Derivatives
- Pancuronium (is active the longest)
- Rocuronium (is active for a long time)
- Vecuronium
- [A PeRVe]
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Where are Aminosteroid derivatives metabolized?
- in the liver
- if a patient has a diseased liver an alternative NMB or drug dose might have to be used
- ALL NMBs are filtered through renal system; something to keep in mind during dosage
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Benzylisoquinoline Derivatives
- Atracurium
- Cisatracurium
- [BAC or CAB]
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How are Benzylisoquinoline derivatives metabolized?
- by organ INDEPENDENT elimination
- therefore they might be a better NMB choice (than aminosteroids) if a patient has liver or kidney failure
- can further decide between cisatracurium (seems to last longer) or atracurium by looking at what side-effects each result in
- eg. atracurium is less favorable because → laudanosine (seizures) & histamine release
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Laudanosine
- a metabolite of the non-depolarizing NMB atracurium that produces tachycardia & potential seizure-like activity
- atracurium is a benzylisoquinoline derivative
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What are some therapeutic uses of non-depolarizing NMBs?
- skeletal muscle relaxation for surgical procedures or as an adjuvant to anesthesia
- to maintain synchrony in mechanically ventilated patients
- to prevent shivering during hypothermia protocols
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Non-depolarizing NMB Duration of Action
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Adverse effects of Non-Depolarizing NMBs
- 1. tachycardia & hypertension due to vagolytic + sympathomimetic properties (pancuronium, rocuronium)
- 2. histamine release potentially leading to: hypotension, reflex tachycardia, flushing, urticaria, bronchospasm (atracurium)
- 3. Acute Quadriplegic Myopathy Syndrome (AQMS)
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Acute Quadriplegic Myopathy Syndrome (AQMS)
- preferential loss of the motor protein myosin & myosin-associated thick filament proteins in ICU patients characterized by severe muscle weakness & atrophy of spinal nerve innervated limb & trunk muscles that can go on for days or weeks
- risk of getting AQMS from NMB use increases if steroids are also being taken
- occurs more often in prolonged use (longer surgical procedures) or long ventilation times & can increase morbidity
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How can a non-depolarizing NMB blockade be reversed?
- 1. by increasing the concentration of ACh: it will have a higher chance of occupying a nAChR site than the drug
- 2. by giving AChase inhibitors (eg. neostigmine): decreasing ACh breakdown helps increase the amount of ACh in the synaptic cleft
- #2 is not as effective for “deep blockade”; is more effective when 4/4 TOF twitches occur
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What is the main kind of Depolarizing NMB?
- Succinylcholine - comprised of two ACh molecules
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Phase I Block of Depolarizing NMBs
- succinylcholine binds to a nAChR, opening of the receptor's channel, depolarizing the motor end-plate, & Ca2+ is released from the sarcoplasmic reticulum causing fasciculation
- succinylcholine doesn't dissociate from the nAChR, maintaining the membrane potential above threshold preventing the muscle cell from repolarizing
ACh cannot propagate an action potential on an already depolarized end-plate & succinylcholine is fairly resistant to degradation by AChase
as the calcium is independently reuptaken by the sarcoplasmic reticulum, the muscle relaxes → paralysis
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fasciculation
a small, local, involuntary muscle contraction, aka a "muscle twitch"
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Phase II Block of Depolarizing NMBs
- the end-plate eventually repolarizes, but because succinylcholine is not metabolized like ACh, it continues to occupy the nAChRs
- this “desensitize” the motor end-plate making it impossible to depolarized again
- this phenomenon is rarely seen in clinical practice b/c it only occurs w/ prolonged or repeated use of succinylcholine, resulting in paralysis that can last 30 – 60 minutes
- phase II is similar to how non-depolarizing NMBs act
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What is responsible for metabolizing succinylcholine?
- butyrylcholinesterase
- this enzyme is not readily availably in the NMJ synaptic cleft which explains why the more succinylcholine that's used, the longer it takes to degrade & the longer paralysis lasts
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What effect do depolarizing NMBs have on ACh's binding to pre-synaptic NMJ nicotinic receptors?
- twitch height is reduced in a constant manner but no “fade phenomenon” is seen
- this means the effect of succinylcholine can't be effectively monitored during paralysis
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What is succinylcholine mainly used for?
- to facilitate endotracheal intubation
- rocuronium (a non-depolarizing NMB) can also be used for this purpose
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Adverse effects of Depolarizing NMBs
- Hyperkalemia
- Masseter muscle rigidity
- Bradycardia
- Malignant hyperthermia
- Muscle pain (usually the day after surgery)
- Prolonged paralysis from butyrylcholinesterase deficiency
- Anaphylaxis
- Increased intragastric pressure
- Increased intra-ocular pressure
*why succinylcholine isn't used unless for rapid sequence intubation
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Malignant Hyperthermia
- high fevers & rigidity that can quickly lead to death if untreated
- can have a genetic predisposition to it
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Can succinylcholine (the depolarizing NMB) be reversed?
- not readily because succinylcholine & ACh have essentially the same mechanism of action
- in fact, their effect is augmented by AChase inhibitors (AChase is already not effective at breaking down succinylcholine, now with less enzyme available it would be even worse → longer lasting paralysis)
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General Sequence of Muscle Paralysis
- small, rapid muscles (eye) > limbs, neck, trunk, masseter, & upper airway > intercostal muscles, larynx, & face > diaphragm
- larger muscles (eg. diaphragm) are more resistant to block
- paralysis fades in the REVERSE order → the diaphragm regains function 1st
- the sequences = the same for both types of NMBs
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Characteristics of All NMBs
- they don't alter level of consciousness or pain sensation
- have poor oral absorption → must be given intravenously
- they IONIZE & don't cross the BBB
- their duration of action is the time from administration to the time when the evoked neuromuscular function of the thumb returns to 25% of baseline
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What effect do inhalation anesthetics have on a NMB blockade?
they reduce postsynaptic receptor sensitivity to ACh & therefore decrease muscle contractility
eg. desflurane > sevoflurane > isoflurane > halothane > nitrous oxide
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What effect do antibiotics have on a NMB blockade?
- they decrease presynaptic ACh release
- reduce postsynaptic nAChR sensitivity
- impair ion channels
- eg. Aminoglycosides, Colistin, Clindamycin, Tetracyclines
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What effect do calcium channel blockers & local anesthetics have on a NMB blockade?
they reduce postsynaptic receptor sensitivity to ACh which leads to decreased muscle contractility
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