NMDRs Flashcards
NMJ Transmission Function
- ACh synthesized and stored in synaptic veicles
- AP stimulates distal motor nerve
- Ca++ diffuses into terminal and VGCaCh open
- synaptic vesicles fuse to membrane
- ACh released into cleft
- presynaptic nicotinic receptor responds to ACh by synthesizing more and mobilizing ACh vesicles (+ feedback)(phII block w Sux related to this)
- ACh binds to nicotinic ACh receptors on surface of post-synaptic membrane
Cholinergic
releases ACh
Adrenergic
releases NE
Pre/Post Ganglionic NTs
PNS pre and post = ACh
SNS pre = ACh
SNS post = NE
ACh is hydrolized by ____ to ____ and _____
ACh is hydrolized by acetylcholinesterase (AChE) to acetate and choline
- choline taken up by presynaptic terminal for resynthesis of ACh
- acetate diffuses away
The release of NT is dependent on the entry of Ca++
HYPOcalcemia = decreases NT release (weakness)
HYPERcalcemia = increases NT release (tetany)
HYPOmagnesemia = increases NT release
HYPERmagenesemia = decreases NT release
- the actions of Ca++ and Mg+ are antagonistic at presynaptic nerve terminals
ACh receptors - A subunits
both A subunits must be occupied to get contraction! Block one = no contraction. Sux lands on both and we get depolarization
Up-regulated AChRs (denervation injuries - burns)
– AChr agonists see increased sensitivity
– AChr antagonists see decreased sensiCvity
• Nondepolarizing muscle relaxants (NDMR) are AChr antagonists
– These patients require increased dosages or shorter redosing intervals of the NMDRs
anesthesia on a burn patient requires frequent redoxing due to upregulation of receptors!
Down-regulated AChRs (myasthenia gravis)
– ACHr agonists see decreased sensitivity and require higher dosages
– ACHr antagonists see increased sensitivity and require lower dosages and longer intervals between redosing
our NMDRs are ANTagonists therefore we require higher AGonists
Depolarizing Muscle Relaxants (Sux)
- depolarize the nACHr - NOT competitive
- action similar to ACh (ACh depolarizes the NMJ and is rapidly metabolized by AChE)
Sux (depolarizing)
- attaches to the 2 A subunits and depolarizes
- metabolized by BCH-esterase (not present in the NMJ)
- after depolarization, sux remains in the synaptic cleft until plasma level lowers and creates a concentration gradient out of the cleft
- after moving out of the cleft, circulating BCH-esterase metabolizes the remaining sux.
- 80-90% of the sux is metabolized in the blood on the way to the NMJ! (so only 10-20% of the dose is giving us action)
NON-depolarizing muscle relaxants
- competitive: compete for ACh binding sites on nicotinic receptor
- when bound, it prevents ion channel from opening
- NDMRs completely BLOCK ACh from binding to receptor… post-synaptic membrane remains polarized
Non-Depolarized Block
- is from competitive inhibition of nAChR
- shows fade on TOF monitor
- can see post-tetanic facilitation (increase in TOF after tetanic stimulation)
- can be antagonized (reversed) by anticholinesterases
- do NOT see fasiculations (no depolarization)
Succinylcholine
DOA: ultrashort
Onset: 0.5-1.5 min
Duration to 25% recovery: 6-8 min
ED95: 0.25 - 0.30
SE: histamine release, tachycardia (brady in peds), decresed BP
Atracurium
DOA: Intermediate
Onset: 3-4 min
Duration to 25% recovery: 35-45 min
ED95: 0.15 - 0.25
SE: dose-dependent histamine release, small reflex tachycardia, minimal BP effect
Cisatracurium
DOA: Intermediate
Onset: 5-7 min
Duration to 25% recovery: 35-45 min
ED95: 0.05
SE: no effect on HR, BP, no histamine release
Vecuronium
DOA: Intermediate
Onset: 3-4 min
Duration to 25% recovery: 35-45 min
ED95: 0.05
SE: no histamine release, minimal BP and HR effect
Rocuronium
DOA: Intermediate
Onset: 1-1.5 min
Duration to 25% recovery: 30-40 min
ED95: 0.30
SE: no histamine release, minimal tachy in kids, minimal BP effect
Mivacurium
DOA: Short
Onset: 3-4 min
Duration to 25% recovery: 15-20 min
ED95: 0.08
SE: dose-dependent histamine releae, minimal HR and BP effect
What is the purpose of giving muscle relaxants?
- to relax the skeletal muscles… more importantly to relax the VOCAL CORDS to pass the ETT through
What are the benefits of muscle relaxation?
- improve surgical conditions (CV, neuro, transplant surgeries)
- facilitate endotracheal intubation
What are the risks associated with muscle relaxation?
- no analgesia
- no anesthesia
- paralyzed but not anesthetized = bad!
ED50 of muscle relaxant
dose at which a muscle relaxant produces a 50% depression of twitch tension in the nACHr
A depolarizing NMB (sux) does 3 things:
- desensitizes the nACHr
- inactivates the VGaNa Channel and the NMJ
- increases K+ permeability in the surrounding membrane
* due to these effects, no AP can be generated and AChR blockade occurs!*
Percentages of Twitch Response
- twitch response may not be reduced until 70% of nAChR are blocked
- twitch is completely elminated when 90% of receptors are blocked
Peripheral Nerve Stimulation can answer 3 Questions:
- is NMB adequate?
- is it inadequate?
- can it be antagonized?
- you must know how to use TOF IOT answer these questions!*
Clinical tests to monitor cessation of NMB
- 5 second head lift
- leg lift off OR table
- strong handgrip from which you cannot remove 2 fingers
- TV (only requires return of diaphragmatic tone) can pull 5mL/kg with 80% nAChR still occupied by NMDR
Dibucaine Test
atypical BCE genetic variant, the dibucaine number communicates how inhibited the action of BCE is by dibucaine.
- higher the number the more normal they are
- low dibucaine number = longer DOA for sux
ie: dibucaine number of 20-30 will prolong action of Sux up to 4-8 hours
Treatment of Sux-induced Hyperkalemia
- hyperventilation (make them alkalotic)
- 1-2 mg Ca+ Chloride IV (helps w muscle contraction)
- 50cc D50W + 10 U IV Insulin (adults) or
1 ml/kg D50W + 0.15 U/kg insulin (peds)
- Na+ Bicarb 1 mEq/kg
Dantrolene
Txs MH
- initial dose 2 mg/kg
- repeat 2 mg/kg up to 10 mg/kg if required
- clinical response of decreased temp, decrease ETCO2 will indicate enough dantrolene has been given
- redosing in PACU may be necessary
MH may occur: (3 things)
- after multiple unremarkable anesthetics (previous sux exposure)
- during maintenace phase or post op from anesthesia
- in pts w no prior fam hx of MH
Phase II Block
- excessively large doses, repeat doses of Sux, or Sux infusions can result in a phase II block. This acts more like a non-depolarizing blockade of the NMJ.
- if fade on TOF w a non-depolarizing block, the Sux has gone into a Ph II block.
>20 min reverse
monitor/extubate at 0.9.
Anticholinesterases
Neostigmine, pyridostigmine, etc.
- given to reduce the activity of enzymes that break down ACh to IOT reverse the effects of non-depolarizing muscle relaxants
- standard at end of anesthetic cases
2 groups of non-depolarizing muscle relaxants:
benzylisoquinolinium and
aminosteroid
benzylisoquinolinium
d-tubocurarine (not in US)
metocurine (60 min, not in US)
atracurium (60 min)
cis-atracurium (30-60 min)
doxacurium (60+, not in US)
aminosteroid compounds
pancuronium (60 min)
vecuronium (20-50 min)
rocuronium (most common, 20-50 min)
pipercuronium (60+ min, rarely used)
NDMRs are _____ ______ chemical compounds that are positively charged
NDMRs are quaternary ammonium chemical compounds that are positively charged
