31: Pharmacology Of The NMJ Flashcards
Drugs that modify atonal conduction in therapeutic doses
Very few, besides local anesthetics
Why are pharmaceutical agents that inhibit ChAT of little us?
Uptake of choline is the rate-limiting step in Ach biosynthesis
SNARE proteins
A superfamily of proteins that mediate vesicle fusion
Two families of SNARE proteins
- Vesicle (V-SNAREs)
2. Target (T-SNAREs)
NAchR vs MAchR structure
Nicotinic: ligand-gated ion channel
Muscarinic: G-protein coupled receptor (7 transmembrane domains)
Nicotinic vs muscarinic receptor placement in muscles
Nicotinic: skeletal muscle
Muscarinic: smooth and cardiac muscle
M2 and M3 vs M2 placement
M2 and M3: both on smooth muscle
M2: predominates cardiac muscle
Where in the NMJ are nAchRs found?
Pre-junctional and post-junctional
Pre-junctional nAChRs
Mobilize additional transmitters for subsequent release by moving more Ach vesicles towards synaptic membrane
Three agonists of skeletal muscle nAChR’s
Ach, nicotine, succinyl-choline
Four antagonists of skeletal muscle nAChR’s
D-tubocurarine, atracurium, vecuronium, pancuronium
Antagonist of central and peripheral neuronal nAChRs
Mecamylamine
What happens when Ach binds a nicotinic receptor?
Conformational change in receptor -> opens up for cations to pass through
Why cant negatively charged anions pass through nAChR channels?
Strong negative charges at the mouth of the channel
Tetrodotoxin
Puffer fish poison (not used clinical)
Symptoms of tetrodotoxin ingestion
Occur rapidly after ingestion: weakness, dizziness, parasthesia, hypotension, sometimes generalized paralysis while consciousness is maintained; death due to respiratory failure and hypotension
Botulism
Life-threatening neuroparalytic syndrome due to neurotoxin from Clostridium botulinum -> botulinum toxin
Where is Clostridium botulinum found?
Surfaces of veggies, fruits, seafood, in soil and marine sediment around the world
Botulinum toxicity symptoms
Acute onset of bilateral cranial neuropathies, symmetric descending weakness, no sensory deficits, blurred vision
Food borne botulism symptoms
Nausea, vomiting, abd pain, diarrhea, dry mouth
Clinical uses for botulinum toxin
Strabismus and blepharospam associated with dystonia, cervical dystonia treatment, botox, axillary hyperhidrosis, migraine treatment
What produces tetanus toxin?
Clostridium tetani
Where is clostridium tetani found
Soil
After tetanus toxin binds synaptobrevin in the NMJ, what happens?
The toxin is internalized -> transported retroaxonally to spinal cord -> blocks release of inhibitory neurotransmitters that relax contracted muscles
Tetanus presentation
Spastic paralysis, trismus (lockjaw), autonomic overactive the, stiff neck, board-like rigid abdomen, opisthotonus, dysphagia
How do both agonists and antagonists prevent synaptic transmission by binding nAChRs
Agonists: activate receptor chronically by binding it
Antagonists: bind receptor but do not generate depolarization
What happens with curare poisoning?
Flaccid paralysis
How is curare used clinically?
During anesthesia to relax skeletal muscle
How to reverse paralysis from curare
Increasing Ach in NMJ by using AchE inhibitors
Clinical use of succinylcholine
Induction agent for anesthesia
What does succinylchole cause?
Transient muscle fasciculations (twitching)
How to reverse paralysis caused by succinylcholine
Time - termination of its binding effects
Clinical use of AChE inhibitors
- Dementia tx
- Myasthenia gravis tx
- Reversal of NMJ blockade during anesthesia
- Urinary retention tx
- Also used in insecticide poison
Two clinical uses of Dantrolene
- Treatment of malignant hyperthermia
2. Treatment of spasticity associated with upper neuron disorders (MS, cerebral palsy, CVA, spinal cord injury)
Malignant hyperthermia
Hyper metabolic state after exposure to succinylcholine anesthetic -> excessive Ca causes contractions -> rapid increase in temp + renal failure from rhabdomyolysis
