UMP2004 pharmacology of the neuromuscular junction Flashcards
describe how the presynaptic nerve terminal structure relates to its function
- contains presynaptic vesicles of Ach in the nerve terminal
- only 50% of Ach reaches receptors
- the rest is broken down by acetylcholinesterase
- basement membrane between nerve terminal and postsynaptic cell which houses cholinesterase
-the vesicles fuse at the presynaptic membrane at the active zone which is directly opposite the synaptic folds (increase surface area to receive Ach) - Schwann cell overlies nerve terminal and protects it (non myelinated)
describe how the postsynaptic cell (muscle fibre) structure relates to its function
- synaptic folds increase surface area for Ach receptors
- high density of Ach receptors opposite the active zone
what is a?
vesicles
what is b?
active zone
what is c?
synaptic folds
what is d?
endplate
what is the sequence of events involved in synaptic transmission?
- uptake of precursors
- synthesis of transmitter (e.g. Ach)
- uptake/transport of transmitter into vesicles
- degradation of excess transmitter (e.g. AchE)
- depolarisation of nerve terminal by action potential
- influx of Ca in response to action potential
- fusion to membrane of vesicles and exocytosis of transmitter
- diffusion to postsynaptic membrane
- interaction with postsynaptic receptors (e.g. reach end plate potential, cause muscle twitch)
- inactivation of transmitter
- reuptake of transmitter or degradation productions by nerve terminals
- uptake and release of transmitter by nerve non-neuronal cells
- interaction with presynaptic receptors
- uptake and release
what 7 steps in synaptic transmission can be targeted by drugs?
- uptake of precursor (e.g. choline) into presynaptic nerve terminal
- transmitter synthesis (e.g. choline to Ach by CAT) from precursor
- transmitter packaging into vesicles
- exocytosis of transmitter from vesicle (dependent on Ca influx)
- transmitter binding to postsynaptic receptors (competitive antagonist)
- postsynaptic response (non competitive antagonist)
- transmitter breakdown e.g. AchE
7.
give an example of a drug that blocks uptake of precursor (choline) into presynaptic nerve terminal
hemicholinium
give an example to a drug that blocks the transmitter packaging into a vesicle
- vesamicol
give some examples of drugs that block transmitter release from the presynaptic nerve terminal
- botulinum toxin (botox)
- tetanus toxin
- aminoglycoside antibiotics
give an example of a drug that prevents breakdown of transmitter
- anticholinesterases e.g. neostigmine
give an example of a non-depolarizing/competitive drug that blocks the post synaptic response
tubocurarine, gallamine, pancuronium
give an example of a depolarising drug that blocks the post synaptic response
- suxamethonium
what is the different mechanisms of actions for competitive/non depolarizing and depolarizing blockers?
- competitive/non-depolarizing = compete with ACh for receptor sites
- depolarizing = binds to receptor, activating it (causes sustained depolarisation which inactivates Na channels which generate APs, so no more APs = no response),
how does hemicholinium work?
blocks choline (precursor) uptake into presynaptic nerve terminal
how does vesamicol work?
- blocks Ach from being taken up into vesicles in presynaptic nerve terminal
how does botulinum toxin work?
- blocks the release of Ach by interfering with docking mechanism and Ca activation
how does tetanus toxin work?
- blocks the release of Ach by interfering with docking mechanism and Ca activation
how do aminoglycoside antibiotics effect presynaptic nerve terminal?
- e.g. streptomycin
- interfere with Ca activation, prevent release of Ach from presynaptic nerve terminal
how does suxamethonium work?
- depolarizing blocker
- binds to Ach receptor activating it, causing prolonged depolarisation, inactivating Na channels involved in APs generation = no more APs = no response
what is the importance of autonomic ganglia in terms of pharmacology and muscle receptors?
- the Ach receptors at the NMJ and in autonomic ganglia are all classified as nicotinic
- nicotinic Ach receptors in ganglia differ from those in muscle in their pharmacology
- so drugs that act on ganglia don’t necessarily act on muscle receptors
what are the 5 different nicotinic Ach ganglia receptors?
- motor neuron –> nicotinic Ach skeletal muscle
- parasympathetic –> nicotinic receptor Ach ganglia –> Ach muscarinic (e.g. salivary gland)
- sympathetic –> nicotinic Ach ganglia receptor –> Noradrenaline (e.g. blood vessels)
- sympathetic –> nicotinic receptor Ach ganglia –> Ach muscarinic (e.g. sweat gland, blood vessels)
- sympathetic –> nicotinic receptor Ach on adrenal medulla
give 4 examples of Ach ganglion agonists
- nicotine
- tetramethyl ammonium
- Ach
- carbachol
what it unique about ganglion blockers which makes them unpredicatable?
- they are selective for autonomic ganglia but don’t distinguish between parasympathetic and sympathetic do many effects are undesirable
describe the action of cholinesterases (AChEs)
- 2 active sites:
- anionic site = -ve charged site associated with carboxyl group. initial binding of Ach is ionic attraction between anionic site and cationic head of Ach
- esteratic site = reactive hydroxyl group associated with serine residue, ester group of Ach binds here - Ach binds then is cleaved leaving an acetylated (reactive) enzyme
- remaining bond is hydrolysed leaving choline, acetic acid and reactive enzyme
what are the 2 sites on cholinesterase?
- anionic site = -ve charged site associated with carboxyl group. initial binding of Ach is ionic attraction between anionic site and cationic head of Ach
- esteratic site = reactive hydroxyl group associated with serine residue, ester group of Ach binds here
how do short-acting reversible cholinesterase blockers work?
- they have a similar structure ti Ach
- bind weakly to AchE
- +ve charge binds only to the anionic site (not esteratic site)
- used to identify muscle weakness, not used for treatment
give an example of a short-acting reversible cholinesterase blocker
- edrophonium
how do long-acting reversible cholinesterase blockers work?
- very similar structure to Ach
- charged group binds to anionic site and carbamyl group binds to esteratic site
- gets cleaved
- hydrolysis of carbamyl group is very slow so AchE cant go on to break down other Ach molecules
give an example of a long-acting reversible cholinesterase blocker
- neostigmine, pyridostigmine
how do irreversible cholinesterase blockers work?
- pentavalent phosphorous molecules
- at low concentrations, bind reversibly to esteratic site (not anionic site)
- at high concentrations it binds irreversibly to esteratic site
- this releases hydrofluoric acid
- forms irreversibly phosphorylated AChE which can not break down Ach
- there are some reactivators however to try to reverse this effect (antidote)
give some examples of irreversible cholinesterase blockers
- DYFLOS/DFP = nerve gases used by army
- Novichok
give some examples of reactivators of phosphorylated cholinesterase ( antidote to Ach targeted poisons)
- pralidoxime - NMJs peripherally
- diacetyl mono oxime - brain, crosses BBB + atropine to combat central excitatory effects
