NMJ Transmission Function
- Nerve synthesizes ACH and stores it in synaptic vesicles
- AP stimulate the distal motor nerve:
1. Ca2+ diffuses in terminal and VGCa2+ channel opens
2. synaptic vesicles fuse to the presynaptic membrane
3. Ach is released into the cleft
4. Presynaptic nicotinic receptor responds to the presence of Ach by synthesizing more and mobilizing ACH vesicles (+ feedback) - —prevents depletion of Ach at NMJ
- —phase II blockade seen w/ SUX related to this
5. ACH binds to the nicotinic ACHr’s not the surface of the post-junctional membrane
NMJ Transmission Function (6)
- during nerve AP
- Na+ flows into cell and depolarizes the vgCa2+ channels
- Ca2+ influx triggers the release of Ach
- Ach combines with post synaptic nicotinic receptors
- Both alpha subunits must be occupied to open the ion channel (na+ and Ca2+ diffuse IN, K diffuses out)
- Ca2+ influx continues until depolarization and the channels inactivate
Ach is hydrolyzed by ___________
-Ach-esterase (AchE) to choline and acetic acid (choline is taken up by presynaptic terminal for resynthesis of ACH)
Release of NTM’s dependent upon
Entry of Ca2+
Hypocalcemia: decreases NTM release
Hypermagnesia: decreases NTM release
Hypercalcemia: increases NTM release
Hypomagnesemia: increases NTM release
actions of Ca and Mag are antagonist at presynaptic nerve terminals
Ach receptors
alpha3beta2: neuronal, presynatpic nerve ending
2alpha1betadeltaE and the alpha 7: fetal– post synaptically, during development and denervation, and in immobilization and burn injury
In upregulated Achrs
(denervation injuries-burns)
- AchR agonists see increased sensitivity
- Achr antagonists see decreased sensitivity
- –non depolarizing muscle relaxants are AChr antagonists
- these patients require increased dosages or shorter reducing intervals of the NMDRs
In 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
Depolarizing Muscle Relaxants
- depolarize the nACHr- NOT competitive
- depolarizing muscle relaxants action similiar to ACH (Ach depolarizes the NMJ and is rapidly metabolized by ACHesterase
- SUX attaches to the 2 alpha subunits and depolarization
- SUX is not metabolized by Ach-esterases, but by BCH-esterase- NOT present in the NMJ
- after depolarization, SUX remains in the synaptic cleft until plasma levels lowers and creates a concentration gradient out of the cleft
- when it moves out of the cleft, circulation BCH-esterase metabolizes the remaining SUX
- about 80-90% of SUX dose is metabolized in the blood on the way to the NMJ
NONdepolarizing
competitive block- compete for ACH binding sites on the nicotinic receptor
- when NDMR binds to the Anchor it prevents the ion channel from opening
- NDMRs completely block Ach from binding to receptor: post synaptic membrane remains polarized
- shows fade on TOF monitor
- can see post titanic facilitation (increase in TOF after tetanic stimulation)
- can be antagonized (reversed) by anticholinesterases)
- do NOT see fasiculations (no depolarization)
Metabolism of NMJ: Biliary excretion negligible (4)
Succ
Mivacurium
Atracurium
Cistatracurium
Metabolism of NMJ: Biliary Excretion primary (2)
Vecuronium
Rocuronium
Primary Metabolism of NMJ (4)
Succ
Mivacurium
Atracurium (2/3 by hydrolysis, 1/3 by hoffman)
Cistaracurium
Secondary Metabolism of NMJ (2)
Vecuronium
Rocuronium
