Drugs Acting at the NMJ

Question 1

Where is AChE located?

Answer 1

Postsynaptically.

Question 2

Major uses of AChE inhibitors

Answer 2

To diagnose and treat MG. To treat AD. To reverse the effect of NMJ blocker.

Question 3

Myesthenia Gravis caused by?

Answer 3

Antibodies directed at nAChR, also can be due to antibodies against MuSK (which is a kinase involved in nAChR clustering).

Question 4

Rate limiting step in acetylcholine breakdown?

Answer 4

Hydrolysis of acetyl-AChE bond

Question 5

3 Classes of AChE inhibitors

Answer 5

Competitive inhibitors (no change in enzyme)
Carbamates (reversible inhibitors)
Organophosphates (irreversible soon after binding) – SLUDGE

Question 6

How to recover from organophosphate poisoning

Answer 6

Synthesis of new receptor. Has quaternary amine (is charged) to prevent crossing at BBB, reduced risk of seizures.

Question 7

Neostigmine

Answer 7

Carbamate used to treat myesthenia gravis. 50% metabolized in liver, rest excreted from kidney

Question 8

What do you need to give with neostigmine?

Answer 8

Atropine (mAChR antagonist) to ensure prevent systemic symptoms.

Question 9

Neostigmine vs physostigmine

Answer 9

Neostigmine has quaternary amine to prevent it from crossing BBB and causing seizures

Question 10

Pyridostigmine

Answer 10

First-line anticholinesterase used in MG. Less frequent dosing than neostigmine. 80-90% eliminated by kidney

Question 11

Edrophonium

Answer 11

Degraded by plasma esterases, so only acts for a few minutes. Is diagostic of MG.

Question 12

Anticholinesterases to treat alzheimers dementia have this is common:

Answer 12

Tertiary amines, so they cross BBB.

Question 13

Three anticholinesterases used to treat dementia

Answer 13

Galantamine (also directly agonizes nAChRs)
Donepezil
Rivastigmine

Question 14

Unique things about the anticholinesterases used to treat dementia

Answer 14

Galantamine and donepezil (hepatic excretion), but galantamine is not so heavily protein bound (better in liver disease)
Rivastigmine is eliminated in the brain.

Question 15

Major uses of neuromuscular blockers

Answer 15

To relax skeletal muscles during surgical procedures, tracheal intubation and mechanical ventilation. Also to prevent dislocations during electroconvulsive therapy.

Question 16

How to NMJ blockers produce paralysis?

Answer 16

Non depolarizing blockade- competitive antagonists of ACh binding to nAChR.

Depolarizing blockade- nicotinic agonists that produce sustained membrane depolarization, and therefore inactivation of VG Na Channels

Question 17

Characteristics of Non-depolarizing blockers (3)

Answer 17

Permanently ionized so don’t penetrate BBB
Distribution is mostly restricted to blood (small Vd)
Resistant to degradation by acetylcholinesterase.
Longer acting –excreted by kidney
Shorter acting –metabolized by liver or plasma cholinesterases.

Question 18

Tubocurarine

Answer 18

Non-depolarizing NMJ blocker, no BBB crossing

Question 19

Cisatracurium

Answer 19

Non-depolarizing. Non enzymatic degradation. Lasts 25-45 mins, no toxic metabolites

Question 20

Mivacurium

Answer 20

Non-depolarizing, lasts 10-25 mins, shortest lasting. Degraded by cholinesterases.

Question 21

Pancuronium

Answer 21

Steroid NMJ blocker, non depolarizing. Long duration of action (longer than 35 minutes)

Question 22

Rocuronium

Answer 22

Steroid NMJ blocker, 20-35 minutes. Better than Pancuronium because it has a blocker

Question 23

Why is Rocuronium better than Pancuronium?

Answer 23

It can be completely blocked by sugammadex.

Question 24

Succinylcholine

Answer 24

Depolarizing NMJ blocker. Has 2 ACh’s linked. Agonist at nAChR, but resistant to AChE so sustained activation. Inactivates Na and Ca channels. Two phases of paralysis

Question 25

Two phases of succinylcholine paralysis

Answer 25

Phase 1: Depolarization blockade, cant be reversed by AChE inhibitors, would only further depolarize membrane.

Phase 2: Membrane repolarizes but remains flaccid, thought that nAChRs become desensitized to succinylcholine, can be reversed by anticholinesterases.

Question 26

Succinylcholine PK

Answer 26

Limited to blood because highly charged. Rapidly degraded by plasma cholinesterases.

Question 27

Onset for IV administration of Succinylcholine

Answer 27

30-60 sec, lasts 4-6 minutes

Question 28

Onset of IM administration of Succinylcholine

Answer 28

Onset in 2-3 minutes, duration of 10-30 minutes

Question 29

Train of Four

Answer 29

Non-depolarizing NMJ blockers inhibit autoreceptors, so cause fade during train. Depolarizing blockers have diminished but constant for phase 1, then fade for phase 2.

Question 30

How do general anesthetics affect NMJ blocker action?

Answer 30

Potentiation! Be careful.

Question 31

Malignant hyperthermia

Answer 31

Can happen when general anesthetic administered with succinylcholine. Caused by excessive Ca release from SR, treated with Dantrolene.

Question 32

How do antibiotics affect NMJ blocker action

Answer 32

Many antibiotics reduce stimulation induced ACh release, so potentiation also.

Question 33

Why do burn victims require higher doses of NMJ blockers?

Answer 33

Because they are functionally denervated, so there’s an upregulation of nAChRs.