Kruse DSA: agents that act on the NMJ Flashcards
What are the nondepolarizing neuromuscular blocking drugs?
- atracurium
- cisatracurium
- doxacurium
- metocurine
- mivacurium
- tubocurarine
- Pancuronium
- pipercuronium
- rocuronium
- vecuronium
What is the ONE depolarizing neurmuscular blocking drug?
-succinylcholine
Muscle relaxants?
- Dantrolene
- Botulinum toxin
Acetylcholinesterase inhibitors
- abenomium
- donepezil
- echothiophate
- edrophonium
- galantamine
- neostigmine
- physostigmine
- Pyridostigmine
- rivastigmine
- tacrine
Antimuscarinic compunds
- atropine
- glycopyrrolate
Cholinesterase reactivators
-pralidoxime
What do nondepolarizing NM blocking agents do?
- act as antagonists of the nAChR
- prototype: d-tubocurarine
What do depolarizing NM blocking agents do?
- blockad by excess of a depolarizing agonist (ACh)
- prototype: succinylcholine
What are all NM blocking drugs structurally similar to?
-acetylchoine… makes sense
How must NM blocking drugs be administered?
-parenterally because they are highly polar and inactive orally
PK of nondepolarizing NM blocking agents?
- fast distribution, slow elimination
- poor solubility
- if excreted by kidney, longer half life than when excreted by liver
- all steroidal muscle relaxants are metabolized to active metabolites
MOA for ND (non depolarizing) NM blocking agents?
- competitive antagonists at the nAChR
- least potent have fastes onset and shortest duration of action
- larger muscles recover better and are most resistant
How doe we reverse the NM blockade?
- add ACh! a natural agonist of the nAChR
- or succinylcholine
What cholinesterase inhibitors could we had to reverse effects of NM blockade?
-pyridostigmine or neostigmine
What is coadministered with cholineesterase inhibitors to minimize adverse cholinergic effects caused by increase in ACh concentration at mAChRs?
-Anticholinergic agents like glycopyrrolate or atropine
Adverse effects of Nondepolarizing agents?
- histamine release (bronchospasms and hypotension)
- d tubocurarine causes a lot of this so we don’t use it anymore
What do anesthetics do with NM blockade?
-potentiate it
How do abx react with NM blockings
-aminoglycosides enhance NM blockade
-
In what disease is NM blockade by nondepolarizing muscle relaxants enhanced?
-myasthenia gravis
Atracurium
- intermediate-acting NM blocker
- inactivated by spontaneous breakdown (hoffmann elimination)
- Laudanosine will cause seizure bc it crosses BBB
- usually short term use in OR so nbd
- *less histamine release than other nondepolarizing agents
Cisatracurium
- intermediate acting stereoisomer of atracurium with fewer side effects
- can be used even with significant renal and hepatic impairment
- virtually devoid of CV effects
Doxacurium
- long acting ND muscle relaxant eliminated by the kidney
- not often used because of the long-l;asting effects as well as high degree of elimination by the kidney (not used in pts with renal failure)
- no CV effects
Mivacurium
- Shortest duration of action, slower onset of action than succinylcholine
- if you use toomuch to speed onset, get profound histamine release and subsequent CV effects
- metabolism by plasma cholinesterase (pt’s with renal failure have less of this)
Steroid derivatives
-the intermediate active steroid muscle relaxants (vecuronium, rocuronium) tend to be more dependent on biliary excretion or hepatic metabolism for their elminiation and are more likeyl to be used clinically than long acting steroid relaxants (pancuronium pipecuronium
What are all steroidal muscle relaxants metabolized to?
- hydroxy derivatives
- they are usually less potent than the parent drug
- usually not an issue, only if it’s used for a long time… then it causes prolonged paralysis because of longer half life than the parent compound
What do the steroidal nm blocking agents have the least tendency to cause?
-histamine release
Rocuronium
- has most rapid time of onset, is of intermediate duration, and lower potency
- rapid onset allows it to be used as an alternative to succinylcholine in rapid-induction anesthesia and in relaxing the laryngeal and jaw muscle to facilitate tracheal intubation
What is the only depolarizing blocking drug used clinically?
-Succinylcholine
PK of succinylcholine
- ultra short duration
- plasma cholinesterase has high capacity to hydrolyze it, so not much gets to the nm junction
- not effectively metabolized at the synapse by acetylcholinesterase
Pharmacodynamcis of succinylcholine
-the nm effect of it are similar to ACh, except that it produces a longer effect at the nm junction compared to ACh
What is Phase 1 block (depolarizing)
- after activating the naCHR, depolarization of the motor end plate spreads to adjacent membranes causeing muscle contraction
- the depolarized membranes remain depolarized and unresponsive to subsequent impulses
- because excitation-contraction soupling requires end plate repolarization and repetitive firing to maintain muscle tension, flaccid paralysis results
- Phase 1 depolarizing block is augmented, not reversed, by cholinesterase inhibitors
Phase 2 block (desensitizing)
- continued exposure to succinylcholine causes the initial end plate depolarization to decrease and the membrane becomes repolarized
- the membrane is unable to be depolarized because the receptor is desensitized
- although this mechanism is unclear, the channels behave as if they are in a prolonged closed state similar to nondepolarizing block
what is the phaase 2 desensitizing block reversed by”
-ACh inhibitors
What happens at first when we administer succinylcholine?
-muscle fasciculations
What is succinylcholine used for?
-rapid induction for quick surgical procedure where an ultrashort acting nm blocker is practical
How do we reverse the nm blockade made by succinylcholine?
- it gets rapidly degraded by plasma cholinesterases
- so WE don’t do much, the body does
Adverse effects and contraindication of succinylcholine
- CV: watch out if you’re using atropine or something anticholinergic like that
- Hyperkalemia: if severe burns… cardiac arrest
- Increased intraocular pressure
- increased intragastric pressure… increases risk for regurgitation
- muscle pain
What is the black box warning with succinylcholine?
-rarely, acute rhabdomyolysis with hyperkalemia followed by ventricular dysrhythmias, cardiac arrest, and death can occur after administration to apparently healthy children with an undiagnosed skeletal muscle myopathy
Succinylcholine drug-drug interactions
-anesthetics: malignant hyperthermia, caused by abnormal release of Ca2+ stores in skeletal m….. tx with Dantrolene
Do NM blocking agents cross the BBB?
- no
- that is why we can use them to tx convulsions
What are the spasmolytic agents againg?
- dantrolene
- Botulinum toxin
Dantrolene
- not centrally acting
- interferes with excitation-contraction coupling in the muscle fibers
MOA of dantrolene
- inhibition of RyR calcium channel
- muscle contraction impaired
- cardiac and smooth muscle unaffected due to a different RyR channel subtype
side effects of dantrolene
-generalized muscle weakness, sedation, and occasionally hepatitis (contraindicated in pts with hepatitis)
What is dantrolene used for?
-tx of upper motor neuron disorders and management of malignant hyperthermia
MOA of Botulinum toxin
- cleaves the SNARE complex and blocks the release of ACh by preventing vesicle exocytosis
- Local injection of botulinum toxin has become a useful tx for genrealized spastic disorders, such as cervical dystonia and blepharospasm
Which enzyme is responsible for hydrolysis and metabolism of succinylcholine circulating in plasma and is also one of the enzymes responsible for cocaine metabolism?
-Butyrylcholinesterase
Where is Acetylcholinesterase found?
-at the postsynaptic end plate of the nm junction where it provides immediate removal of ACh
What are the 3 subgroups of AChE inhibitors?
- alcohols: edrophonium
- Carbamic acid esters: the stigmines
- Organophosphates: nerve gases… high CNS toxicity…. lipid soluble
Which subgroup binds to AChE irreversibly and covalently?
-Organophosphates
What determines the duration of actions for AChE inhibitors?
-the stability of the inhibitor-enzyme complex rather than by metabolism or excretion
Which kinds of AChE inhibitors are the toxic ones with CNS distribution?
-Teriary and uncharged AChE inhibitors
which ones are really good insectisides?
-organophosphates
-they are readily absorbed from the skin, lung, gut, and conjunctiva
-wide distribution
-
What does the eye look like when given parasympathetic stimulation?
- pupile is contracted
- sphincter muscle of iris is contracted
- ciliary muscle is contracted for near vision
What happens at the NMJ with AChE inhibitors?
- makes things contract
- profression of depolarizing nm blockade to non depolarizing nm blockade like with succinylcholine
What are the standard AChE inhibitors used in the symptomatic tx of myasthenia gravis?
- Pyridostigmine
- neostigmine
- Ambenonium
- *they do not cross BBB
What is the Edrophonium test?
- used as diagnostic agent for myasthenia gravis
- temporarily relieves the ptosis, difficulty speaking and swallowing, and extremity weakness associated with the disease
- due to dangers with this, we use the ice pack test instead… which temporarily inhibits cholinesterase enzyme activity
What are we distinguishing between with the edrophonium test?
- Myasthenic vs. Cholinergic crisises
- if the patient is in myasthenic crisis, the sypmtoms will improve
- if the condition is cholinergic crisis, the symptoms will remain unchanged or woresen
What can reverse the paralysis induced by nm blocking drugs during surgical anesthesia?
-AChE inhibitors
What else can AChE inhibitors be used for?
-to treat paralytic ileus, atony of the urinary bladder, and congenital megacolon
How AChE inhibitors treat glaucoma
- reduce IO pressure by stimulating mAChRs of the ciliary body and causing contraction, which facilitates outflow of the aqueous humor
- therapy with AChE inhibiotrs has been replaced by topical B-blockers and PG derivatives
how AChE inhibitors are used to treat dimentia
- pts with dementia of Alzheimer type have deficiency of intact cholinergic neurons
- tacrine was approved to tx this, but b/c of high hepatotoxicity, newer agents are good (like physostigmine)
- Pts with dementia associated with parkinson disease also benefit
If there is intoxication due to anticholinergic agents, what will that present like?
-cutaneous vasodilation, anhidrosis, anhydrotic hyperthermia, nonreactive mydriasis, delirium, hallucinations, and a reduction or blocked mAChR stimulation
Which drug is preffered to tx anticholinergic intoxication?
- Physostigmine
- it crosses the BBB
Will AChE inhibitors diminish or augment the nm blockade made by nondepolarizing nm blocking agents?
- diminish it
- the exception is with mivacurium, where the nm blockade is prolonged
AChE inhibitors rxn with suyccinylcholine
-enhanced phase 1 block and antagonize phase 2 block
AChE inhibitors rxn with cholinergic agonists
- direct acting agents act predominantly on mAChRs
- combo with AchE inhibitors will enhance the effects of cholinergic agonists
AChE inhibitors rxn with systemic corticosteroids
-coadministration with AChE inhibitors may enhance muscle weakness seen in pts with myasthenia gravis
What are the signs of AChE intoxication?
- miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea
- with poisoning from lipid soluble agents, CNS involvement follows rapidly
what is the main cause of death with cholinergic intoxication
-respiratory failure
What is the antidote recommended for cholinergic poisoning?
-the mAChR antagonist atropine
What do we use to regenerate AChE at the NMJ?
-cholinesterase regenerators!
what is the cholinesterase regenerator we need to know about?
-pralidoxime
What do cholinesterase regenerators do?
-regeneate active enzyme via removal of a phosphorous group from the active site of the enzyme
What do we have to make sure we give cholinesterase regenerators before?
-before aging has occurred between the organophosphate and cholinesterase
What can we do for prophylaxis in AChE inhibitor poisoning?
- give them pyridostigmine
- this was approved for combat use in US military personnel
What tx regimen should begin at the first sign of nerve gas exposure?
- parenteral atropine, pralidoxime, and a benxodiazepine as an anticonvulsant
- drop the pyridostigmine when you see this
What are the common side effects of pyridostigmine prophylaxis?
-stomach cramps, diarrhea, nausea, frequent urination, headaches, dizziness, SOB, worsening of peptic ulcer, blurred vision, and watery eyes
