Lecture 33: Drugs of NMJ Flashcards Preview

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Flashcards in Lecture 33: Drugs of NMJ Deck (34):
1

All AChE inhibitors do what?

Increase concentration of ACh at synapse

2

What are the 3 classes of AChE inhibitors?

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

3

Mechanism of competitive inhibitors and 3 key drugs

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

4

Mechanism of Carbamates (reversible inhibitors) and 4 key drugs

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

5

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

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

6

Major uses for anticholinesterases (3)

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

7

Physostigmine

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

8

Neostigmine

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

9

Pyridostigmine

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

10

Edrophonium

Very short acting; uses: diagnostic test for myasthenia gravis

11

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

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

12

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

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

13

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

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

14

How is rivastigmine eliminated?

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

15

How is galatamine gallant?

Dual action: potentiates signaling at nAChRs independently of AChE inhibition

16

Neuromuscular blockers definition and major use

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

17

Describe the two mechanisms that NMJ blockade produce paralysis

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

18

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

True

19

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

Degradation by acetylcholinesterase

20

Tubocurarine (curare)

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

21

Cisatracurium

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

22

Mivacurium

Degraded by pseudocholinesterase; 20 min duration (shortest)

23

Pancuronium

Duration: 35 min

24

Rocuronium and antagonist

Steroid NMJ blocker metabolized by liver; sugammadex

25

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

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

26

What is the Train of Four?

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

27

Describe general anesthetics and NMJ blockade

Can potentiate a NMJ block

28

Describe malignant hyperthermia and NMJ blockade

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

29

Describe antibiotics and NMJ blockade

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

30

What are some adverse effects of succinylcholine?

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

31

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

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

32

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

Cholinesterase inhibitors + antimuscarinics to counter parasympathetic side effects

33

How to reverse a NMJ blockade for a depolarizing blocker

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

34

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

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

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