Lecture 15: Pharmacology of the Neuromuscular Junction (DSA+CIS)

Question 1

What do you call transmitters that utilize Acetylcholine?

Answer 1

Cholinergic

Question 2

What does the enzyme choline acetyltransferase do?

Answer 2

Synthesis of choline and acetyl CoA to make Acteylcholine

Question 3

In Alzheimer’s Disease, what enzyme deficiency do they have?

Answer 3

Choline acetyltransferase

Leads to decreased ACh production

Question 4

What happens to newly syntheszied Acetylcholine?

Answer 4

ACh is shuttled into sorage vesicles via ACh vesicular transporters.

Question 5

How does ACh leave the vesicles?

Answer 5

• Calcium enters the cell and depolazies the membrane
  
  • The vesicles with ACh move toward pre-synaptic membranes and fuse with them
• VAMPs and SNAPs assist the fusion and release of ACh
  
  • ACh is released into synaptic cleft via exocytosis

Question 6

What blocks the fusion of ACh vesicles to the pre-synaptic membrane?

Answer 6

Botulinum Toxin

• Heterogenous group of gram-positive, spore-forming anaerobic bacteria
• Can be found on vegetables, fruits, seafood. this bacteria exists in soil and marine sediment.

Question 7

How is ACh recycled back into the pre-synaptic cell?

Answer 7

• Acetylcholinesterase cleaves ACh into choline and acetate
• ACh returns via choline transporter
• Endocytosis can also reclaim ACh molecules

Question 8

What are some key differences between Nictonic and Muscarinic ACh receptors?

Answer 8

Nicotinic Acetylcholine Receptor (Ionotropic)

• Found on Skeletal Muscles
• Ligand Gated Ion Channel
  
  • Super fast (milliseconds)

Muscarinic Acetylcholine Receptor (Metabotropic)

• Found on Smooth and Cardiac Muscles
• G-protein Coupled Receptor
  
  • Second Messenger
  • Measured in seconds

Question 9

How do nicotinic ACh receptors select for positively charged ions to let through?

Answer 9

The inside of the receptor’s channel is coated with negative charges

Example: Aspartic Acid and Glutamic Acid

Question 10

Tetrodotoxin

What is its mechanism?

How can you come into contact with this toxin?

Answer 10

• Mechanism: Inhibition of voltage gated sodium channels
  
  • Can lead to paralysis, weakness, and even death (high dose)
• From puffer fish poison (more seen in Japan)

Question 11

Local Anesthetics

What is its mechanism?

Where do you see it being used?

Answer 11

• Mechanism: Inhibition of voltage gated sodium channels
• Can be used for many clincal procedures

Lidocaine, Bupivacaine, Procaine

Question 12

Botulinum Toxin

What is its mechanism?

What are its symptoms?

How can it be used clincally?

Answer 12

• Mechanism: Cleaves components of the SNARE complex, preventing ACh release
  
  • Can cause bilateral cranial neuropathies associated with symmetric descending weakness
  • Foodborne anaerobic bacteria: nausea, vomiting, abdominal pain, diarrhea
• Clincial Use: Improve wrinkles and prophylaxis of chronic migraine headaches

Question 13

Tetanus Toxin

What is its mechanism?

What are its symptoms?

Where does it come from?

Answer 13

• Mechanism: Blocks fusion of synpatic vesibles by targeting synaptobrevin and prevents release of inhibitory neurotransmitters
  
  • Causes spastic paralysis (e.g. lockjaw)
• Origin: Clostridium tetani produces this toxin and is found in the soil.

Question 14

Curare Alkaloids (d-tubocurarine)

What is its mechanism?

What can it be used for?

Answer 14

• Mechanism: Antagonist that competes with ACh and can decrease size of action potential
  
  • Relaxes skeletal muscles during anesthesia

Competes with ACh and does not lead to an action potential

Question 15

How would you reverse the effect of a Curare Alkaloid?

Answer 15

Increase the amount of ACh in the neuromuscular junction

Ex: Utilize an acetylcholinesterase inhibitor

Question 16

Succinylcholine

What is its mechanism?

What is it used for?

Answer 16

• Mechanism: An agonist that depolarizes nicotinic nACh receptors and can cause continued depolarization
  
  • Receptor is blocked and can cause paralysis
  • Can cause muscle fasciculations (twitch)
• Used as an induction for anesthesia
  
  • ​Takes much longer than ACh to break down
    
    • ACh: broken down in milliseconds
    • Succinylcholine: broken down in minutes
• Eventually reversed by time

Question 17

Cholinesterase Inhibitor

What is its mechanism?

What is it used for?

Answer 17

• Mechanism: Binds to and inactivates acetylcholine esterase, increaseing ACh at NMJ
• Clinical Use:
  
  • Treatment of nerve gas and pesticide exposure
  • Myasthenia Gravis
  • Reversing neuromuscular blockade during anesthesia

Question 18

Dantroline

What is its mechanism?

What is the clincal use?

Answer 18

• Mechanism: Ryanodine (RyR) inhibitor that stops muscle contraction by blocking calcium release
  
  • Inhibits ACh release
• Clincal Use:
  
  • ​Treatment of malignant hyperthermia, since the elevation of body temperature is related to muscle contractions
  • Treats muscle spasms

Question 19

What is Myasthenia Gravis?

Answer 19

Immune Disorder: Antibodies against nicotinic ACh receptors

• Weakness and fatigue
• Worsens with activity and better with rest
• Symptoms
  
  • Ptosis, droopy eyelids
  • Jaw Fatigue

Question 20

Malignant hyperthermia?

What is this condition?

What can happen if left untreated?

How can you treat this?

Answer 20

• Fast rise in body temperature and severe muscle contractions
  
  • Hyper metabolic repsonse
• Patients w/ this disease can see a mutation in Ryanodine Receptor (deals with Calcium storage)
• If left untreated, can lead to kidney failure
• Treat with Dantrolene