What are these small vesicles lining the post synaptic membrane?
When analyzing the neuromuscular junction in a muscle, you count the number of nACh receptors on the post-synaptic membrane and get 10. How many molecules of ACh are necessary to open the channel?
20. There are two binding sites (alpha subunits) for ACh on a nAChR, both of which must be occupied to open the receptor. There is also a beta, a delta and an epsilon subunit.
What are the two classes of neuromuscular blockers?
Non-depolarizing NMJ blockers (competitive with ACh) and depolarizing NMJ blockers (agonist)
What are the different non-depolarizing NMJ blockers?
d-tubocurarine is the prototype and is very long acting and seldomly used.
What must be present for a non-depolarizing NMJ blocker to be an effective drug?
ACh. Non-depolarizing NMJ blockers are antagonists, which means they are only effective when the agonist (ACh) is present. If you stimulate the muscle directly it will still contract.
What happens to the efficacy of non-depolarizing NMJ blockers as time progresses after their administration?
Non-depolarizing NMJ blockers stimulate anticholinesterases, which increases the amount of ACh at the NMJ. Increases concentrations of ACh then outcompete non-depolarizing NMJ blockers at the post-synaptic nAChRs.
What is the key mechanism of depolarizing NMJ blockers?
They are resistant to AChE and persist at the NMJ, prolonging the depolarization of the membrane. Since the membrane is depolarized, the muscle cannot be stimulated at all.
You decide to give a patient succinylcholine in the operating room in conjunction with neostigmine. Why would you do this?
Succinylcholine is a phase I blockade, meaning that it keeps the channel open and prolongs depolarization of the membrane to promote paralysis. Increasing the concentration of ACh at the membrane will increase the amount of depolarization.
What is a key difference regarding phase II depolarizing NMJ blockers?
The muscle repolarizes and drugs are surmountable by increasing ACh concentrations.
What serious side effect are patients with nerve damage particularly susceptible to if they are given succinylcholine?
Hyperkalemia. When a muscle is dennervated, it expresses many more embryonic nAChRs as it waits for new innervation. Administration of succinylcholine hits many more nAChRs than normal, causing a greater than normal efflux of K+, causing hyperkalemia.
Why do patients sometimes experience prolonged apnea after administration of succinylcholine?
It decreases plasma cholinesterase activity
A patient is given succinylcholine and halothine during a heart surgery and his temperature begins to rise drastically from this combination of drugs. What would the anesthesiologist administer to control his temperature?
Dantrolene. It acts on the muscle to decrease Ca2+ release from the sarcoplasmic reticulum and inhibits the excitation-contratction coupling.
Compare the different qualities of non-depolarizing blockers, phase I depolarizing blockers and phase II depolarizing blockers.
Why do you administer atropine when trying to reverse the effects of a non-depolarizing NMJ blocker?
These blockers are reversed by anticholinesterase because it causes ACh to build up at the NMJ. This build up is harmful at the mAChRs of the autonomic nervous system, especially in the heart, and atropine prevents the autonomic effects of anticholinesterases.
A patient is recovering post-op and has full function of his thumb. When would he regain breathing function so he can come off of a ventilator?
Prior to the thumb recovery. Larger muscles recover faster from NMJ blockers.
What do you see when stimulating muscle after administration of non-depolarizing blockers vs. phase I vs. phase II blockers?
How do NMJ blockers work with anesthetics?
Non-depolarizers (tubocurarine) potentiate anesthetics (isoflurane) so you don't have to use so much anesthetic.
How do NMJ blockers work with local anesthetics (Ca2+ channel blockers)?
Blocking influx of Ca2+ into the presynaptic terminal potentiates the effects of NMJ inhibitors blocking the post-synaptic receptors.
When would you use depolarizing vs. non depolarizing NMJ blockers?
Succinylcholine (depolarizing) is eliminated very quickly because it is broken down by plasma cholinesterase's. The non-depolarizing NMJ blockers last longer.
What is the major side effect you need to keep an eye out for when using NMJ blockers during surgery?
Activation of mast cells and histamine side effects.
What bacteria produces BoNT?
What is the site of action of botulin toxin?
How often do you need to repeat botox injections?
Every 3-6 months, the nerve reinnervates the muscle in that time.
What are clinical uses for botulinum toxin?
Spasms (ocular, esophageal, vocal cord), excessive armpit sweating and chronic migraines.
What is the most common form of myasthenia gravis?
Autoimmune form. Antibodies bind nAChRs and induce internalization of the receptor.
How do you diagnose myasthenia gravis?
Tensilon test, it is a short-acting AChE inhibitor. Use neostigmine and immunosuppressants for long term maintenance.