31: Pharmacology Of The NMJ

Question 1

Drugs that modify atonal conduction in therapeutic doses

Answer 1

Very few, besides local anesthetics

Question 2

Why are pharmaceutical agents that inhibit ChAT of little us?

Answer 2

Uptake of choline is the rate-limiting step in Ach biosynthesis

Question 3

SNARE proteins

Answer 3

A superfamily of proteins that mediate vesicle fusion

Question 4

Two families of SNARE proteins

Answer 4

1. Vesicle (V-SNAREs)

2. Target (T-SNAREs)

Question 5

NAchR vs MAchR structure

Answer 5

Nicotinic: ligand-gated ion channel
Muscarinic: G-protein coupled receptor (7 transmembrane domains)

Question 6

Nicotinic vs muscarinic receptor placement in muscles

Answer 6

Nicotinic: skeletal muscle
Muscarinic: smooth and cardiac muscle

Question 7

M2 and M3 vs M2 placement

Answer 7

M2 and M3: both on smooth muscle

M2: predominates cardiac muscle

Question 8

Where in the NMJ are nAchRs found?

Answer 8

Pre-junctional and post-junctional

Question 9

Pre-junctional nAChRs

Answer 9

Mobilize additional transmitters for subsequent release by moving more Ach vesicles towards synaptic membrane

Question 10

Three agonists of skeletal muscle nAChR’s

Answer 10

Ach, nicotine, succinyl-choline

Question 11

Four antagonists of skeletal muscle nAChR’s

Answer 11

D-tubocurarine, atracurium, vecuronium, pancuronium

Question 12

Antagonist of central and peripheral neuronal nAChRs

Answer 12

Mecamylamine

Question 13

What happens when Ach binds a nicotinic receptor?

Answer 13

Conformational change in receptor -> opens up for cations to pass through

Question 14

Why cant negatively charged anions pass through nAChR channels?

Answer 14

Strong negative charges at the mouth of the channel

Question 15

Tetrodotoxin

Answer 15

Puffer fish poison (not used clinical)

Question 16

Symptoms of tetrodotoxin ingestion

Answer 16

Occur rapidly after ingestion: weakness, dizziness, parasthesia, hypotension, sometimes generalized paralysis while consciousness is maintained; death due to respiratory failure and hypotension

Question 17

Botulism

Answer 17

Life-threatening neuroparalytic syndrome due to neurotoxin from Clostridium botulinum -> botulinum toxin

Question 18

Where is Clostridium botulinum found?

Answer 18

Surfaces of veggies, fruits, seafood, in soil and marine sediment around the world

Question 19

Botulinum toxicity symptoms

Answer 19

Acute onset of bilateral cranial neuropathies, symmetric descending weakness, no sensory deficits, blurred vision

Question 20

Food borne botulism symptoms

Answer 20

Nausea, vomiting, abd pain, diarrhea, dry mouth

Question 21

Clinical uses for botulinum toxin

Answer 21

Strabismus and blepharospam associated with dystonia, cervical dystonia treatment, botox, axillary hyperhidrosis, migraine treatment

Question 22

What produces tetanus toxin?

Answer 22

Clostridium tetani

Question 23

Where is clostridium tetani found

Answer 23

Soil

Question 24

After tetanus toxin binds synaptobrevin in the NMJ, what happens?

Answer 24

The toxin is internalized -> transported retroaxonally to spinal cord -> blocks release of inhibitory neurotransmitters that relax contracted muscles

Question 25

Tetanus presentation

Answer 25

Spastic paralysis, trismus (lockjaw), autonomic overactive the, stiff neck, board-like rigid abdomen, opisthotonus, dysphagia

Question 26

How do both agonists and antagonists prevent synaptic transmission by binding nAChRs

Answer 26

Agonists: activate receptor chronically by binding it
Antagonists: bind receptor but do not generate depolarization

Question 27

What happens with curare poisoning?

Answer 27

Flaccid paralysis

Question 28

How is curare used clinically?

Answer 28

During anesthesia to relax skeletal muscle

Question 29

How to reverse paralysis from curare

Answer 29

Increasing Ach in NMJ by using AchE inhibitors

Question 30

Clinical use of succinylcholine

Answer 30

Induction agent for anesthesia

Question 31

What does succinylchole cause?

Answer 31

Transient muscle fasciculations (twitching)

Question 32

How to reverse paralysis caused by succinylcholine

Answer 32

Time - termination of its binding effects

Question 33

Clinical use of AChE inhibitors

Answer 33

1. Dementia tx
2. Myasthenia gravis tx
3. Reversal of NMJ blockade during anesthesia
4. Urinary retention tx
5. Also used in insecticide poison

Question 34

Two clinical uses of Dantrolene

Answer 34

1. Treatment of malignant hyperthermia

2. Treatment of spasticity associated with upper neuron disorders (MS, cerebral palsy, CVA, spinal cord injury)

Question 35

Malignant hyperthermia

Answer 35

Hyper metabolic state after exposure to succinylcholine anesthetic -> excessive Ca causes contractions -> rapid increase in temp + renal failure from rhabdomyolysis