succinylcholine question, please clarify - cancer_84

[ArchivalUser]

Kaplan said that Succinylcholine effect is not reversed by AChE inhibitors, meaning AChE inhibitors can prolong phase one but do not reverse phase 2,

but FA and UW said that Neostigmine can reverse phase 2, and prolongs phase 1


can someone clarify for me??


thans sooo much

Merry Christmas everyone ))

[ArchivalUser]

Hi cancer84,

For the exam I would stay with FA + UW. Unfortunately KLN don't have any published errata, and I think that item would need a clarification note;

If you go to a reference pharmacology textbook, you can find that the result on phase II is quite unpredictable, and should be done with caution. - Goldman & Gilman 12th ed, it's on page 260.

There is a book "Case Files Pharmacology" - it's directed to the USMLE preparation, and has a case in pg 35 only about that issue. (the book is from 2014- 3rd edition)
As I know your exam is near I will transcribe some parts of that case for you. (wait a minute I will post it right away…)

GL in your Exam!

[ArchivalUser]

ok, it start as malignant hyperthermia and then it unravels to drug description and end up with short questions. ( I know you don't have problem with malignant hyperthermia, but I will put it complete here, maybe could help other people too. But you can skip reading and go direct below the line I will put after this part, ok)

CASE 4 - "case files pharmacology"
Summary: A 25-year-old man develops muscle rigidity, tachycardia, and high fever during surgery.

Mechanism of action of succinylcholine: Nicotinic receptor agonist at the motor endplate of the neuromuscular junction, which causes persistent stimulation and depolarization of muscle cells.
Reaction that is occurring: Malignant hyperthermia.
Drug given for treatment and its mechanism of action: Dantrolene, which acts by interfering with calcium release from the sarcoplasmic reticulum.

CLINICAL CORRELATION
Succinylcholine is the only depolarizing neuromuscular agent in wide clinical use. It is used for the rapid induction of a brief flaccid paralysis. It works as an agonist of the nicotinic receptor at the motor endplate of the neuromuscular junction. This causes a persistent stimulation and depolarization of the muscle, preventing stimulation of contraction by ACh. It has a rapid
onset and short duration of action because it is quickly hydrolyzed by plasma and liver cholinesterase.

Malignant hyperthermia, a rare but significant cause of anesthetic morbidity and mortality, is an inherited autosomal dominant disorder that results in tachycardia, muscle rigidity, and high body temperatures in response to the use of certain inhaled anesthetics in combination with muscle relaxants, usually succinylcholine. It is caused by a release of calcium ions from the sarcoplasmic reticulum in muscle cells. Dantrolene interferes with this release and is therefore the treatment of choice for this condition.

Succinylcholine is the prototype for depolarizing agents and used for brief paralysis for surgery and for intubation.
Tubocurarine, the prototype, and other nondepolarizing agents (eg, cisatracurium, vecuronium, rocuronium) are used for longer term paralysis for surgery.
In addition to malignant hyperthermia, succinylcholine administration may result in hyperkalemia, particularly in patients with burn and trauma, which could result in cardiac arrest. Myalgia is also commonly reported. It is contraindicated in patients with neuromuscular disease, such as myasthenia gravis and muscular dystrophy, as well as in stroke. Bradycardia may also occur, but can be prevented by pretreatment with atropine.
Certain nondepolarizing agents may produce hypotension, as a result of histamine release and some ganglionic blocking activity, and tachycardia as a result of vagolytic activity. The effects of nondepolarizing agents may be reversed by the acetylcholinesterase inhibitor, neostigmine.
Numerous drug interactions between neuromuscular blocking agents and other drugs have been reported that lead to increased neuromuscular blockade, particularly with certain antibiotics and inhaled anesthetics.

--------------------------------
Structure
The neuromuscular blocking agents resemble ACh (succinylcholine contains two linked ACh molecules) and contain one or two quaternary nitrogens that limit entry into the CNS.

Mechanism of Action
After a single dose, succinylcholine occupies the nicotinic receptor to produce a persistent endplate depolarization (phase I block) that results in flaccid paralysis because the muscles become unresponsive to endogenously released ACh. The initial depolarization is accompanied by muscle fasciculations. Continued exposure of endplates to succinylcholine results in their repolarization. However, through an unclear mechanism, they become relatively insensitive to subsequent depolarization (so called desensitization, or phase II block).
Nondepolarizing blocking agents act as reversible competitive antagonists that block the action of ACh at nicotinic cholinoreceptors in muscle endplates and autonomic ganglia. In contrast to succinylcholine, which has a duration of action of about 6–10 min, the nondepolarizing agents have a longer duration of action (up to an hour).

Cholinesterase inhibitors (eg, neostigmine, pyridostigmine) can effectively antagonize and reverse the neuromuscular blocking action of nondepolarizing agents and succinylcholine during phase II. However, they will augment the action of succinylcholine during phase I.

Administration
The neuromuscular blocking agents are highly polar and therefore must be administered parenterally. Most non depolarizing agents are eliminated through the kidney. Succinylcholine is eliminated by the hydrolytic action of plasma butyrylcholinesterase (pseudocholinesterase).

Pharmacokinetics
Neuromuscular blocking agents are highly ionized and therefore have limited volume of distribution and limited access to the CNS.

COMPREHENSION QUESTIONS
1 The use of succinylcholine as an adjunct to general anesthetics during surgery is based on its ability to:
A. Block the action of ACh at the motor endplate
B. Increase release of ACh from autonomic ganglia
C. Increase release of histamine from mast cells
D. Inhibit cholinesterase

2 Continued exposure of muscle endplates to succinylcholine results in their:
A. Conversion to ion channels
B. Enhanced sensitivity to ACh
C. Regeneration of ACh receptors
D. Repolarization

3 Cholinesterase inhibitors can reverse the action of which of the following?
A. Cisatracurium
B. Succinylcholine
C. Both A and B
D. Neither A nor B

4. A 35-year-old man undergoes surgery for a hernia repair. After the surgery, he complains of diffuse muscle aches, which the anesthesiologist states is likely caused by the skeletal muscle relaxant. He has a temperature of 37.8°C (100°F). Which of the following is the most accurate statement?
A. The agent also commonly causes hypokalemia.
B. The agent blocks ACh at the nicotinic receptor.
C. The agent causes persistent endplate depolarization and desensitization.
D. The patient likely has malignant hyperthermia.

Answers:
A. Succinylcholine acts like ACh to cause depolarization of the muscle endplate. However, unlike ACh, succinylcholine is not metabolized at the synapse. Therefore, the endplate remains depolarized and unresponsive to endogenous ACh, resulting in muscle paralysis.

2 D. Continued exposure of the muscle endplate to succinylcholine results in desensitization (phase II block) where the endplate repolarizes but cannot readily be depolarized.

3 C. Cholinesterase inhibitors like neostigmine can effectively antagonize and reverse the neuromuscular blocking action of nondepolarizing agents and succinylcholine during phase II. However, they will augment the action of succinylcholine during phase I.

4 C. Myalgia is a common adverse reaction of depolarizing agents such as succinylcholine; these agents also may induce hyperkalemia and malignant hyperthermia.

[ArchivalUser]

thank you so much!!!


I really appreciate your help ))) I wish you Merry Christmas...

Good luck with studying ) enjoy it

[ArchivalUser]

Thank you @rush2014

[ArchivalUser]

To my knowledge, phase 1 effect of succinylcholine has no antidote, but phase 2 can be treated with acetylcholinesterase inhibitors because it will compete with the succinylcholine from binding to the receptors again during the desensitization phase 2.

Here's a great video that explains all of this perfectly! From what I understand, phase 1 effect of succinylcholine is when succinylcholine originally binds to the nicotinic receptor and acts as a partial agonist that causes a strong constant depolarlizing effect due to not being able to be broken down that well because of low levels of pseudocholinesterase. Remember that acetylcholine is broken down by acetylcholinesterase, whereas succinylcholine is broken down by pseudocholinesterase. Because this is taking place in the synaptic cleft at the postsynaptic membrane, the levels of pseudocholinesterase is very low, compared to in the plasma everywhere else. Because of this, you get phase 1 causing tons of muscle twitching (fasciculations). The next phase is when the succinylcholine is unbound but because of such a powerful response to the depolarlization signals, you have receptor desensitization as a defense to this so now you end up with the originally wanted muscle paralysis.

https://www.youtube.com/watch?v=NSq0baJ8YA8