15. Muscle relaxants Flashcards
What is a motor unit?
What are the features of alpha fibres?
What is the speed of nerve conduction?
Multiracial neurone and muscle fibres it innervates (10-100’s of fibres)
Alpha fibres are around 10mcm, have myelin sheath and nodes of ranvier with voltage gated sodium channels.
Conjunction = 50-100m/s
What is saltatory conduction?
High speed due to impulses jumping down nodes of ranvier
Describe the NMJ and what occurs during stimulation of muscle contraction?
Motor nerve terminates at end plate (terminal bouton)
Depolarisation activates VG Ca channels (N-type) on pre-synaptic
Ca entry triggers AcH release from vesicles
Ach binds to nicotinic Ach receptors on. Uncle increasing permeability of ligand gated Na channels
Causes depolarisation and when threshold reached this propagates along the muscle
What is Lambert Eaton and what do we see?
Antibodies to N type Ca channels at NMJ.
See initial muscle weakness with increased strength on repetitive movement
What is the formulation of Ach?
What synthesises it?
Contains a quaternary ammonium ion and an ester link
Choline is found in meat and eggs
Acetyl group from anaerobic decarboxylation of pyruvate by acetyl-coa
Synthesis by choline acetyltransferase
Where are AcH vesicles found?
How are they secured?
How much do they release?
Some free in cytosol and some membrane tethered by snare proteins
Quantum is released in response to AP. Size of quanta varies according to number of vesicles docked and frequency of AP’s.
How is AcH release regulated?
By presynaptic nicotinic Ach receptors (NaChR’s) - structurally different from post synaptic
Activation increases release
TOF fade is thought to be due to these
What are MEPPs?
What are EPP’s?
Mini end plate potentials
- Random vesicle exocytosis without AP’s causing small transient depolarisations, not enough to reach threshold.
Endplate potentials
- enough AcH released to reach threshold and open nicotinic channels
What is the formation of post synaptic nicotinic receptors?
What causes opening and what happens?
What ions move through them and what does this do to membrane potential?
Ligand gated with 5 subunits round a central ion channel
Two alpha, one beta, one gamma and one epsilon
Two AcH binding sites (between A-G and A-E) and both need filled to cause conformational change
Alpha subunits rotate to open channels
Na can move in (145 outside and -5 inside)
na Nernst potential = +50, so MP moves from -85mV to +15
Potassium also moves out
Relatively small number need to be activated to reach threshold, so NMB’s need to occupy 80% for block
What affects NAChR numbers?
What happens when this happens?
Up regulation with reduced traffic e.g. burns, cord transaction, prolonged immobility, sepsis and GBS.
- proliferation of junctional and creation of extra junctional
- these are foetal type with y instead of e, that causes longer channel opening
Down regulation
- nicotine (centrally)
- early Alzheimer’s (central + can use cholinesterases)
- organophosphates
What happens if sux is used in situations where there is NAChR upregulation?
Increased K release and more chance of arrhythmia/arrest
What removes AcH?
What happens to channels once it is removed?
AChE which is loosely anchored in post synaptic folds.
- esterases that cleaves ester link
Channels are refractory whilst changing back to initial conformation. This is called the desensitised state.
What is seen when we give a depolarising NMB?
Fasciculations due to activation
Rapid flaccid paralysis
Longer refractory period from desensitisation
What type of drug is sux?
Structure?
Charge?
Ach receptor agonist
2 AcH molecules back to back through acyl CH3 groups
- permanently charged choline groups at either end attracted to AcH sites
- charged ends = water soluble, so no crossing of BBB/placenta
What happens when we give sux, in terms of:
Onset?
Receptor blockade?
Metabolism?
Offset?
Iv 90% metabolised before reaching NMJ
- only 10% of receptors need to be activated to depolarise from -70 to -50 which is enough
- rapid 90% laryngeal block within 50s
Metabolism:
- two ester links cleaved by plasma cholinesterases (pseudo and butrylcholinesterase)
- not in cleft like AChE so takes longer (usually AcH lasts under 10ms)
- metabolised to succinylmonocholine and choline then succinicacid and second choline
Offset:
- Recovery beings in 3m
- complete by 12-15m
- potentiated by volatiles
