DRUGS AFFECTING NMJ TRANSMISSION Flashcards
How can we block NMJ transmission?
Inhibit ACh (choline uptake) presynaptically
Inhibit ACh release presynaptically
Interfere with AChR postsynaptically
What types of things can block nmj and what is their mechanism of action?
Anticholinesterases - affect AChE and affect choline reuptake presynaptically
Toxins/local anaesthetics which block ACh release
Depolarising and non-depolarising blockers which affect the postsynaptic ACh receptor
Examples of inhibitors of ACh release
Local anaesthetic
General inhalation anaesthetics
Inhibitors/competitors of calcium such as magnesium and antibiotics (aminoglycosides gentamicin and tetracycline)
Neurotoxins such as botulinum and beta-bungarotoxin
What are ACh release inhibitors used for
Endotrachael intubation
Surgical procedures as lessens concern of general anaesthetic needed
Allow mechanical ventilation in intensive care
Electroconvulsive therapy
What types of ACh receptors are there
Muscarinic ACh
Nicotinic ACh
What kind of receptor is muscarinic and what types are there?
G protein coupled
M1,3,5 excitatory
M2,4 inhibitory
What kind of nicotinic receptors are there and what type of receptor are they
Ligand gated ion channels
N1 in MNJ
N2 in autonomic / parasympathetic nervous system
Excitatory only
Where are muscarinic receptors not found
Sympathetic nervous system
Where else are nicotinic ACh receptors found
Skeletal NMJ
Sympathetic and parasympathetic
Autonomic ganglia
CNS
How do acetylcholine receptors work? What is their structure?
Chemically controlled sodium channel that opens when ACh binds- causes depolarisation
alpha, ACh, y, alpha, ACh, delta, beta
Agonists of the AChR
Nicotine
Suxamethonium
Decamethonium
These are depolarising blockers
Antagonists of the AChR
Tubocurarine
Atracurium
These are non-depolarising blockers
How do antagonists/non-depolarising blockers work
Work by preventing ACh binding to site
Decrease motor EEP
Decrease depolarisation level of end plate
No activation of action potential
How do agonists/depolarising blockers work
Attach to AChR and not metabolised by AChE
Long depolarisation of end plate
Prolonged EEP
Prolonged depolarisation of muscle membrane
Membrane pot above threshold for testing voltages gated sodium channels so channels remain refractory
No more action potential generated
Non-depolarising blockers
Mivacurium Atracurium Rocuronium Vecuronium Pancuronium
Side effects of depolarising blocker suxamethonium and how are they caused
Bradycardia (muscarinic agonist effect)
Cardiac dysrhythmias inc k+ conc
Raised interoccular pressure (nicotinic agonist effect)
Postop myalgia (muscle fasciculations)
Malignant hypothermia (ryanodine receptor related)
Examples of anticholinesterase drugs?
Neostigmine
Pyridostigmine
Dyflos
Parathion
How do anticholinesterase drugs work
Inc availability of ACh by Dec segregation by AChE
What are neostigmine and pyridostigmine and how do they work
Quaternary amines
Work by forming carbamylated enzyme complex which slows rate of hydrolysis
What are dyflos and parathion and how do they work
Organophosphate anticholinesterase drugs
Work by irreversible inhibition by phosphorylation into highly stable complex
Can be coaxed off by pralidoxime
What is pralidoxime and what is its function
Coaxes irreversible inhibiting anticholinesterase drugs dyflos and parathion from AChE
Duration of cholinesterase degraded drugs are regulated by
Hydrolysis
AChE vs. Plasma cholinesterases
AChE specific to hydrolysis of ACh
Found in conducting tissues and RBCs
Bound to plasma membrane in synaptic cleft
Broad spectrum of substrates wth widespread distribution and soluble in plasma
Side effects of anticholinesterases
CNS
initial excitation with convulsions
Unconscious and respiratory failure
Autonomic nervous system Salivation Lacrimation Urination Defication Gastrointestinal upset Emesis
Bradycardia
Hypotension
Bronchoconstruction
Construction Miosis of pupil
Clinical use of anticholinesterases
Anaesthesia - to reverse non-polarising muscle blockade
Myasthenia gravis- inc NMJ transmission
Glaucoma - Dec interocc pressure
Alzheimer’s - enhance cholinergic transmission in CNS
What are the 2 phases of depolarising blockers
Phase 1
Muscular fasciculations then blockage
Depolarisation inhibited causes K+ leak from cell causing hyperkalaemia
Voltage gated sodium channels kept inactive
Phase 2
Prolonged exposure increased exposure to drug causes desensitisation blockade where depolarisation cannot occur even in absence of drug
What are SRBAs and what do they do?
SRBA are selective relaxant binding agents
Sugammadex
Reverses effect of rocuronium and vecuronium (nondepolarising)
