Lecture 33: Drugs of NMJ

Question 1

All AChE inhibitors do what?

Answer 1

Increase concentration of ACh at synapse

Question 2

What are the 3 classes of AChE inhibitors?

Answer 2

Competitive inhibitors, Carbamates (reversible inhibitors), and Organophosphates (irreversible inhibitors)

Question 3

Mechanism of competitive inhibitors and 3 key drugs

Answer 3

Bind to active site non-covalently and can be displaced by ACh; edrophonium, donepezil, galatamine

Question 4

Mechanism of Carbamates (reversible inhibitors) and 4 key drugs

Answer 4

Undergoes two-step reaction with AChE (like ACh) involving a carbamylated intermediate that blocks ACh from binding; physostigmine, neostigmine, pyridostigmine, rivastigmine

Question 5

Mechanism of Organophosphates (irreversible inhibitors) and 1 key drug and single use

Answer 5

Undergoes two-step reaction with AChE (like ACh) involving a phosphorylated intermediate that is VERY stable; Echothiophate, glaucoma treatment but can cause lens opacities

Question 6

Major uses for anticholinesterases (3)

Answer 6

1. Test for and treat myasthenia gravis; 2. Treat Alzheimer’s disease; 3. Reverse effects of NM blockers

Question 7

Physostigmine

Answer 7

Crosses BBB, rarely used, uses: glaucoma but can cause lens opacity

Question 8

Neostigmine

Answer 8

Does not cross BBB, uses: myasthenia gravis, reverse of NM block, post-op atony

Question 9

Pyridostigmine

Answer 9

Uses: First-line AChE in myasthenia gravis (less frequent dosing than neostigmine)

Question 10

Edrophonium

Answer 10

Very short acting; uses: diagnostic test for myasthenia gravis

Question 11

Describe treatment for myasthenia gravis (first line and if symptoms persist)

Answer 11

FIrst line: AChE inhibitors + antimuscarinic drugs to reduce parasympathetic effects; If persist: treatment to mitigate immune response

Question 12

All anticholinesterases used in dementia do what? How are they effective? What three drugs?

Answer 12

Cross BBB (lipid soluble); modest short-term improvements; donepezil, rivastigmine, galantamine

Question 13

Donepezil and galatamine are both eliminated how? What is important to remember about donepezil?

Answer 13

Hepatically; donepezil is 96% protein bound so it is affected by a decrease in plasma in proteins associated with liver disease

Question 14

How is rivastigmine eliminated?

Answer 14

Plasma cholinsterases, so it’s less likely to interfere with enzyme inhibitors/inducers

Question 15

How is galatamine gallant?

Answer 15

Dual action: potentiates signaling at nAChRs independently of AChE inhibition

Question 16

Neuromuscular blockers definition and major use

Answer 16

Interfere with synaptic transmission by blocking nicotinic receptors of the NMJ; relax skeletal muscle during surgical procedures and ECT

Question 17

Describe the two mechanisms that NMJ blockade produce paralysis

Answer 17

Non-depolarizing blockade: competitive antagonist at ACh binding site of nAChR (can be reversed by increasing ACh concentration via an anticholinesterase) and Depolarizing blockade: nicotinc agonists producing sustained membrane depolarization, inactivating VG-Na+ and Ca2+ channels

Question 18

T/F: All non-depolarizing blockers do not penetrate the BBB

Answer 18

True

Question 19

As a class, non-depolarizing blockers are resistant to what?

Answer 19

Degradation by acetylcholinesterase

Question 20

Tubocurarine (curare)

Answer 20

Used in arrow poison –> death by diaphragmatic paralysis; not available in US

Question 21

Cisatracurium

Answer 21

Spontaneous degradation w/ toxic metabolite that does not normally accumulate; 30 min duration

Question 22

Mivacurium

Answer 22

Degraded by pseudocholinesterase; 20 min duration (shortest)

Question 23

Pancuronium

Answer 23

Duration: 35 min

Question 24

Rocuronium and antagonist

Answer 24

Steroid NMJ blocker metabolized by liver; sugammadex

Question 25

Succinylcholine (which is a…), describe two phases. Which phase is overcomable by AChE inhibitors? Degraded by?

Answer 25

Depolarizing blocker; Phase I: brief period of fasciculations; Phase II: membrane repolarizses yet muscle remains flaccid due to desnsitization to both succinylcholine AND ACh; Phase II; liver

Question 26

What is the Train of Four?

Answer 26

Four stimuli delivered to monitor the NMJ blockade, test should reveal a fade

Question 27

Describe general anesthetics and NMJ blockade

Answer 27

Can potentiate a NMJ block

Question 28

Describe malignant hyperthermia and NMJ blockade

Answer 28

A rare, life-threatening consequence of delivering succinylcholine + inhaled anesthetis caused by excessive Ca2+ release, treated by blocking ryanodine receptor

Question 29

Describe antibiotics and NMJ blockade

Answer 29

Reduce stimulated-induced ACh release, so potentiate effect of non-depolarizing NMJ blockers

Question 30

What are some adverse effects of succinylcholine?

Answer 30

Can stimulate ANS ganglia and cardiac/pulmonary muscarinic receptors; is associated with post-operative muscle pain

Question 31

What are other adverse effects of non-polarizing NMJ blockers?

Answer 31

Histamine release –> hypotension, can cause transient increase in intraocular pressure; can cause blocks at ANS ganglia and cardiac muscarninic receptors

Question 32

How to reverse a NMJ blockade for a non-depolarizing blocker

Answer 32

Cholinesterase inhibitors + antimuscarinics to counter parasympathetic side effects

Question 33

How to reverse a NMJ blockade for a depolarizing blocker

Answer 33

Only reversible in Phase II! Cholinesterase inhibitors + antimuscarinics to counter parasympathetic side effects

Question 34

What population is more sensitive to NMJ blockers? What population is less sensitive?

Answer 34

Myasthenia gravis (fewer nAChRs); burn victims/patients with motor neuron disease (up-regulaton of nAChRs)