Neuromuscular Junction
When two Ach molecules bind to the two alpha subunits of the post-synaptic membrane: what type of receptor does it bind to? What happens after ach binds to this receptor? Which ions move where?
Two Ach bind to a nicotinic receptor on the post-synaptic nerve terminal. It opens the ion channels which allows for Na+ and Ca+ ions to flow in and K+ ions to flow out, all moving down their concentration gradient.
The inflow of these positive ions leads to subsequent action potentials that spreads across the muscle leading to the depolarization and eventually muscle contraction
Describe the relationship between potency and onset time. How does this relate to roc and vec?
Potent NMB's have a high receptor affinity and therefore can be administered in smaller doses. this results in a slower onset time. Less potent NMBs must be given in higher doses and typically have a faster speed of onset
Roc is less potent than Vec, so it has a higher dose (0.6-1.2mg/kg) but it works in 30-60 seconds. Vec is more potent so it only requires 0.1-0.2mg/kg but takes 3 mins to start working.
What are the four most common sites for monitoring NMBs?
- Ulnar nerve
-Temporal branch of the facial nerve
-Posterior tibila nerve
-Common peroneal nerve
**Major limitation exist between peripheral responsiveness to NMBs in comparison with the diaphragm and larynx
How many molecules of a non-depolarizing agent are needed to influence a receptor? When a non-depolarizing agent binds, is it holding the ion channel open or closed? Is it competitive or non-competitively binding?
Only one molecule is needed of a non-depolarizing agent to sufficiently occupy the receptor and prevent it from opening. This is competitive binding.
Which two NMB's are rarely used, though we are still forced to learn them?
Name one reason why each is not commonly used
*bonus points if you can give the dose for each
Atracurium and Pancuronium
Atracurium: causes histamine release; intubation dose is 0.5mg/kg
Pancuronium: can cause significant increases in HR; intubation dose 0.06-0.1mg/kg (average of 0.08mg/kg)
What happens when Ach binds to PRE-synaptic nicotinic receptors? Why is this important for NMBs?
When Ach binds to nicotinic receptors on the presynaptic membrane, this causes the mobilization of more vesicles of Ach so the neuron will be ready to fire again.
This is important because it explains fade. Non-depolarizing NMBs work by antagonizing these receptors, leading to decreased amounts of 'ready-to-go' Ach vesicles. As the supply of Ach vesicles decreases, we see a decreasing reaction to muscle stimulation, seen as fade. (The Apex video on this is stellar)
True!
Rapid injection can speed onset time by generating a high initial concentration. However, in cases using atracurium and mivacurium (?? mentioned in the ppt), rapid injection may be associated with adverse effects of histamine release.
(perhaps this is why we don't use these)
You've given your patient their night-nigh drugs and then their NMB. In what order do you expect these muscles to be affected: intercostal muscles, eyes/fingers, trunk/abdomen, and diaphragm
Small/rapidly moving first (eyes and fingers), then trunk/abdomen, then intercostal muscles, then finally the diaphragm
Termination of action after a single dose is primarily due to redistribution of drug away from the NMJ. After repeated doses the redistribution mechanism becomes saturated.
Vecuronium!!
- What class of NMB?
- Higher or lower potency than rocuronium?
- How is it eliminated?
- Dose? Onset?
- monoquanternary aminosteroid
- higher potency than roc so it has a lower dosing requirement and therefore a slower onset
-Primarily hepatic metabolism and renally excreted
- 0.1-0.2 mg/kg w/ an onset of 3 mins
Which enzyme terminates the effect of Ach? What are the products of the breakdown of Ach? What happens to these products?
Acetylcholinesterase is the enzyme that hydrolyzes Ach to choline and acetate. Choline is reabsorbed by the presynaptic nerve terminal to be made into more Ach, while acetate diffuses away.
True or False: Obesity affects the dose of NMBs.
False! NMBs do NOT cross to adipose tissue and therefore volume of distibution relative to weight is very small. Dose your paralytics based off ideal body weight.
Review:
Male: Ht in cm - 100 = IBW
Female: Ht in cm - 105 = IBW
When only 3 twitches are seen on a TOF, what percentage of receptors can you assume are blocked?
75%!
True or False: Succinylcholine is able to repeatedly bind to different receptors until it is cleared in the plasma.
True! Succinylcholine is NOT metabolized by AchE and can therefore repeatedly bind to different receptors until it is cleared into the plasma
Rocuronium!
- What class of NMB is it?
- What can alter it's onset? What can it do to your VS?
- Intubation dose? RSI dose?
- monoquaternary aminosteroid
- Low cardiac output can increase onset time
- It can ve slightly vagolytic, meaning it can increase your pts HR
- Standard Intubation: 0.6-1.2 mg/kg, RSI: 1.2mg/kg
Other things: preferred for peds, pain on injection, onset 30-60seconds
There are two main types of NMB's. They differ in the way they act on the receptors in the pre and post synaptic membrane. Explain this difference and list which commonly used NMB's are included in each of the two classes.
Depolarizing: succs - works by occupying both subunits of the post synaptic nicotinic receptor (chemical make up is basically two molecules of Ach) and holds the ion channel open. This leads to fasiculation and then flaccid paralysis.
Nondepolarzing: roc, vec, cis (also pancuronium and atracurium) - works by competitively binding to the pre and post synaptic nicotinic receptors. Binding to the post synaptic receptor stops the ion channel from opening. Binding to the presynaptic ion channel leads to fade
There are (at least) four factors that produce resistance to neuromuscular blockers; what are they?
-Burn Injury: caution with succinylcholine due to excess potassium release
- Chronic anticonvulsant therapy: increased clearance and upregulation of receptors
- Denervation: caution with succinylcholine due to excess potassium release
- Myasthenia Gravis: issues with succinylcholine, these patients simply do not have enough receptors to create adequate muscle relaxation, studies show they need about double the regular dose for pts with symptomatic MG
What is the definition of a post-tetanic count? When should you utilize PTC?
Definition: 50Hz tetanus for 5 seconds, a 3 second pause, and then single twitches of 1Hz
Use: Used only when TOF and double burst stimulation are absent; count of less than eight indicates a deep block and prolonged recovery is likely
Describe the difference between a phase I and phase II block. What will you see on the TOF for each?
A phase I block is seen with succinylcholine. Succinylcholine binds to the post synaptic nicotinic receptor and binds much longer than Ach would. This leads to fasiculations (from muscle cells being depolarized and thus contracting) followed by paralysis. No fade is seen on the TOF
A phase II block is seen with all of the non-depolarizing NMB's (AND with succs when it is given in too high of a dose). These non-depolarizing NMB's bind to the post-synaptic nicotinic receptors and competitively inhibit Ach from binding. They also antagonize the presynaptic nicotinic receptors, leading to smaller and smaller amounts of Ach ready to be released. This is what produces the face in the TOF.
Cisatracurium!
- What class of paralytic is it?
- Does it cause histamine release?
- How is it eliminated?
- What is the intubating dose?
- Cis is a benzylisoquinoline
- NO histamine release
- Eliminated by Hoffman elimination (drug of choice for significant liver or renal disease)
- Intubating: 0.2-0.3 mg/kg
* Moderate duration of action with longer onset of action*
What causes extrajunctional receptors? What do these receptors put the patient at risk for? For this reason, which NMB should be avoided?
Denervation injury or prolonged immobility can lead to the proliferation of extrajunctional receptors.
The presence of these receptors predisposes the patient to hyperkalemia.
Avoid succinylcholine in these patients starting 24-48 hours following the injury and for a year after
How does age affect NMBs? How do children's doses differ from adults?
Trick Question!!
- Volume of distribution is larger in children than adults therefore children required a higher dose to achieve a given concentration BUT children's NMJs are more sensitive so a higher dose will prolong the action. These two factors essentially offset and clinically doses are the same per kg as adults
Why can monitoring your NMB using the facial nerve give you an inaccurate reading?
Why do we still use it very commonly?
It is possible to illicit a direct muscle stimulation leading you to believe that your patient needs additional doses of NMB.
We still use it a ton because of ease of access and because it closely resembles the onset time of general neuromuscular blockade when applied appropriately. (Black should be by ear lobe, and red should be 2cm's from eyebrow along facial nerve inferior and lateral to eye)
What is the difference between ester hydrolysis and hofmann elimination? Which drugs use with method of metabolism?
Ester hydrolysis: used to metabolize succinylcholine and mivacurium. Inactivation occurs through enzymatic cleavage. Takes plac in the extracellular compartiment
Hofmann Elimination: Used to metabolize atracurium and cisatracurium (atracurium can also undergo ester hydrolysis). Inactivation occurs by a temperature and pH dependent degradation. Takes place in the central and peripheral compartments and in the synaptic cleft
Succinylcholine:
- Depolarizing or non-depolarizing
- What is it's onset and duration?
- What is it's dose?
- Contraindications
- ONLY depolarizing agent
- Rapid onset with short duration w/ half life of 47 seconds (ideal of RSI or intubation during case where NMB's are not desired)
- RSI dose: 1-2mg/kg
- Contraindications: Neuromuscular diseases, denervation (after 2 days), immobilization (after 3 days), burns (after 2 days), chronic use of muscle relaxants (after 3 days), sepsis/severe inflammation (after 3 days), risk for MH, allergy, or atypical plasma cholinesterase. CVA.