Lecture 33: Drugs of NMJ Flashcards
All AChE inhibitors do what?
Increase concentration of ACh at synapse
What are the 3 classes of AChE inhibitors?
Competitive inhibitors, Carbamates (reversible inhibitors), and Organophosphates (irreversible inhibitors)
Mechanism of competitive inhibitors and 3 key drugs
Bind to active site non-covalently and can be displaced by ACh; edrophonium, donepezil, galatamine
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
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
Major uses for anticholinesterases (3)
- Test for and treat myasthenia gravis; 2. Treat Alzheimer’s disease; 3. Reverse effects of NM blockers
Physostigmine
Crosses BBB, rarely used, uses: glaucoma but can cause lens opacity
Neostigmine
Does not cross BBB, uses: myasthenia gravis, reverse of NM block, post-op atony
Pyridostigmine
Uses: First-line AChE in myasthenia gravis (less frequent dosing than neostigmine)
Edrophonium
Very short acting; uses: diagnostic test for myasthenia gravis
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
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
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
How is rivastigmine eliminated?
Plasma cholinsterases, so it’s less likely to interfere with enzyme inhibitors/inducers
How is galatamine gallant?
Dual action: potentiates signaling at nAChRs independently of AChE inhibition
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
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
T/F: All non-depolarizing blockers do not penetrate the BBB
True
As a class, non-depolarizing blockers are resistant to what?
Degradation by acetylcholinesterase
Tubocurarine (curare)
Used in arrow poison –> death by diaphragmatic paralysis; not available in US
Cisatracurium
Spontaneous degradation w/ toxic metabolite that does not normally accumulate; 30 min duration
Mivacurium
Degraded by pseudocholinesterase; 20 min duration (shortest)
Pancuronium
Duration: 35 min
Rocuronium and antagonist
Steroid NMJ blocker metabolized by liver; sugammadex
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
What is the Train of Four?
Four stimuli delivered to monitor the NMJ blockade, test should reveal a fade
Describe general anesthetics and NMJ blockade
Can potentiate a NMJ block
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
Describe antibiotics and NMJ blockade
Reduce stimulated-induced ACh release, so potentiate effect of non-depolarizing NMJ blockers
What are some adverse effects of succinylcholine?
Can stimulate ANS ganglia and cardiac/pulmonary muscarinic receptors; is associated with post-operative muscle pain
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
How to reverse a NMJ blockade for a non-depolarizing blocker
Cholinesterase inhibitors + antimuscarinics to counter parasympathetic side effects
How to reverse a NMJ blockade for a depolarizing blocker
Only reversible in Phase II! Cholinesterase inhibitors + antimuscarinics to counter parasympathetic side effects
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)
