NMB Antagonism PPT
The effects of anticholinesterase drugs is due to what?
Accumulation of Ach at muscarinic and nicotinic cholinergic receptors
Anticholinergic drugs are selective to what receptors?
Antimuscarinic
Why do anticholinesterase drugs have a ceiling effect?
At a high enough dose, all the enzyme is inhibited. More dose cannot inhibit
When are anticholinesterase drugs administered?
At the end of surgeries (after fascia is closed) to add to rate of spontaneous recovery
Which antimuscarinic is the prototype?
Atropine
What drugs should be available with sugammadex?
Atropine Epi Robinul
Which antimuscarinic agents are naturally occurring and where do they naturally occur?
Atropine and scopolamine Belladonna plant
What are two issues CRNAs should be cautious of when administering ndnmb?
Avoid overdosing Careful when redosing relaxant at case end
If a CRNA must give a patient a neuromuscular blocker before the waiting time is up after reversal with sugammadex, what ndnmb should they use?
Benzilisoquinolones
Anticholinesterase drugs have the BBSLUD side effects. What does BBSLUD stand for and how do you prevent this?
Bradycardia Bronchoconstriction Salivation Lacrimation Urination Defication Administer antimuscarinic med
What are the cardiovascular effects of anticholinesterase drugs?
Bradycardia Decreased MAP (due to decreased SVR)
Where are M1 receptors located? What are their function?
CNS and Stomach Hydrogen ion secretion
What is physostigmine used for?
CNS effects to reduce post op delirium
Where are M3 receptors located? What are their function?
CNS, Salivary, Airway smooth muscle Salivation and Bronchodilation
What are the effects anticholinesterase drugs have on bronchioles and ureters?
Contract
What sort of molecule is edrophonium and why does it act of a shorter duration than the other ndnmb reversal agents?
Edrophonium is a simple alcohol with a quaternary ammonium group. It electrostatically binds to the anionic site is stabilized by hydrogen binding at the esteratic site which is not a true chemical bond. Ach competes for the binding site.
Edrophonium works faster because of what difference between it and neo/pyridostigmine?
Edrophonium works presynaptically Neostigmine and pyridostigmine work post-synaptically
Define the onset of edrophonium, Neostigmine, Pyridostigmine.
Edrophonium- rapid Neostigmine- intermediate Pyridostigmine- delayed
How does use of anticholinesterase differ in neonates and adults?
Elderly- neostigmine and pyridostigmine use prolonged Neonates/peds- Neostigmine dose reduced (edrophonium is not)
What are the effects of anticholinesterase drugs on GI?
Enhanced gastric fluid secretion Increased GI motility Increased PONV
How does Echothiophate inhibit anticholinesterase?
Forms stable inactive phosphorylate complex at esteratic site
Which antimuscarinic agent is synthetic?
Glycopyrrolate
Where are M2 receptors located? What are their function?
Heart and CNS Decreased HR
Anticholinergic meds atropine and robinul do not block bradycardia in which pts? How do you treat bradycardia in these pts?
Heart transplant patients (denervated) Treat with catecholamines
Sugammadex has what unique characteristics that make it effective?
Hollow Has lipophilic and hydrophilic properties
Sugammadex is associated with which negative side effects?
Hypersensitivity and anaphylaxis Bradycardia Cardiac arrest Vomiting Low bp Headache Interferes with contraceptives (oral)
How do electrolyte changes affect reversal?
Hypokalemia and hypermagnesmia make more difficult
What results from undesirable residual block?
Inadequate ventilation leading to respiratory acidosis and hypoxia
What two things can a CRNA do in order to competitively antagonize Ndnmb (non depolarizing neuromuscular blockade)?
Increase Acetylcholine Decrease Ndnmb drug These allow 2 acetylcholine to bind to the receptor
Atropine's effects are most selective for what?
Increased heart rate Relaxed smooth muscle
Glandular effects of anticholinesterase drugs are what?
Increased production in glands innervated by postsynaptic cholinergic fibers Bronchial Lacrimal Sweat Salivary Gastric Intestinal Acinar pancreatic glands
How do anticholinesterase drugs work to reverse muscle blockade?
Inhibiting anticholinesterase increases the half-life of acetylcholine. This increases the concentration in the synaptic cleft and helps to drive the neuromuscular blocker out of the cleft and into plasma.
What factors affect reversal of ndnmb?
Intensity of ndnmb at time of reversal. Agents being reversed Temperature pH Electrolyte changes Drug effects
Anticholinesterase drugs are presumed to be stored where in order to increase the volume of distribution?
Kidneys and liver
The anticholinesterase drugs have a unique volume of distribution. What is unique about it?
Large VoD even though they are poorly lipid soluble
What law dictates the movement of neuromuscular blocker out of the cleft with anticholinesterase drugs?
Law of mass action
How does the agent being used ndnmb affect reversal?
Long acting- 30% residual paralysis Intermediate- 5% residual paralysis Long acting ndnmb-anticholinesterase may wear off before muscle relaxant
Anticholinergic drugs are required to block the undesired response of anticholinesterase drugs at what receptors?
Muscarinic
In regards to dosing anticholinesterase drugs, which cholinergic receptor (muscarinic or nicotinic) effects are elicited at lower doses?
Muscarinic (this is why we have the BBSLUD; require large doses to produce nicotinic skeletal tone)
Which drug is more potent, neostigmine or pyridostigmine?
Neostigmine
What are the three drugs which form carbamylated esters?
Neostigmine Pyridostigmine Physostigmine
In neonates and kids, how do neostigmine and edrophonium differ in dosing?
Neostigmine- decreased Edrophonium- dose remains the same
Arguments for ndnmb reversal?
Neuromuscular margin of safety approved Any degree of residual blockade undesirable Legal considerations
Doses that affect muscarinic receptors have no effect on what receptors?
Nicotinic Autonomic ganglia nicotinic NMJ
Describe the lipid solubility of anticholinesterase drugs?
Poorly lipid soluble due to quaternary amine group except for physostigmine and organophosphates
How does intensity of ndnmb at time of reversal affect reversal?
Profound block takes longer.
Glycopyrrolate is what type of amine?
Quaternary (charged)
How does pH affect ndnmb Reversal?
Respiratory and metabolic alkalosis make difficult
List the five uses of anticholinesterase agents
Reversal of ndnmb Treatment of CNS effects produced by certain drugs Treatment of MG (mestanon is pyridostigmine for this) Treatment of glaucoma Treatment of paralytic ileus and atony of urinary bladder
Name the three classes of anticholinesterase medications
Reversible inhibitors Reversible formation of carbamylated esters Irreversible inactivation by organophosphates
What are three antimuscarinics?
Robinul Atropine Scopolamine
Which muscle relaxant does sugammadex bind the most selectively?
Roc (Lesser extent vec and panc)
Which molecules are engulfed by sugammadex?
Rocuronium Vecuronium Pancuronium (aminosteroids)
The treatment for post op delirium in kids includes what?
Something to drink and their mommy
Name four numbers that can return to baseline with 75-80% of receptors blocked?
TV VC Twitch ht TOF
What are the benefits of mixing anticholinesterase drugs at the end of surgery?
Technically additive not synergistic. However, DO NOT MIX pick one and go with it for this test as Joy stated this in class.
The dose of anticholinesterase reversal given depends on what factor?
The degree of ndnmb
What mechanism causes the carbamylated esters to increase the half-life of Ach in the cleft?
The formation of carbamylated esters form a true covalent bond which is more resistant to hydrolysis
How is the rocuronium-sugammadex complex excreted?
Unchanged by the kidneys
Arguments against ndnmb reversal?
Unnecessary with signs of full spontaneous recovery S/E of reversal agents are undesirable
When is reversal justifiable to avoid?
When considerable time has pass since admin of intermediate ndnmb and signs of full recovery present (argument against is undesirable side effects)
Neostigmine and pyridostigmine form what sort of bond at the esteratic in order to inactivate it?
carbamyl-ester complex (forming carbamylated ester reversible inhibition)
Anitmuscarinics mechanism of action is what?
competitive antagonist at mucarinic cholinergic postganglionic receptor (blocks Ach) without changing the cell membrane
Which cholinergic receptors increase the skeletal muscle tone desired in ndnmb reversal?
nicotinic
Antimuscarinic meds counteract unwanted side effects of NMB. What are the three antimuscarinic drugs used?
robinul Atropine scopolamine
Sugammadex is not recommended for which pts?
severe renal impairment, including those requiring dialysis Women of child bearing age (interferes with birth control)
What is the chemical structure of Atropine and scopolamine?
tertiary amines (uncharged and cross BBB)
What is the number of twitches in TOF to give sugammadex?
two twitches present
Name five muscle relaxant reversal drugs.
Edrophonium Neostigmine Pyridostigmine Physostigmine Sugammadex
What is the minimum waiting time for re administration of rocuronium dose of 1.2 mg/kg after reversal with sugammadex?
5 minutes (dose of 1.2 mg/kg
Sustained tetanus may occur with how many receptors blocked?
50%
How much hepatic metabolism occurs with Neostigmine? Edrophonium? Pyridostigmine?
50% 30% 20%
Anticholinesterase drugs are how much eliminated renally? How does this reflect in pts with renal failure?
50-75% renal elimination Prolonged action in renal failure
What is the duration of action for edrophonium and neostigmine?
60 minutes
What is the duration of action for pyridostigmine?
90 minutes
What is the dose of sugammadex to return TOF to 0.9?
2-4 mg/kg
How many molecules of Ach can acetylcholinesterase hydrolyze?
300,000 per minute
What is the dose for Neostigmine?
0.035 to 0.070 mg/kg
What is the dose for Pyridostigmine?
0.15 to 0.35 mg/kg
What is the dose for edrophonium?
0.15-1 mg/kg
Sustained head lift for 5 second may be possible with how many receptors blocked?
33%
What drug and dose has a minimum waiting time of 4 hours after reversal with sugammadex?
0.6 mg/kg rocuronium 0.1 mg/kg vecuronium
What is the preferred TOF to maintain in order to reverse ndnmb?
1 twitch
What drug and dose has a minimum waiting time of 5 minutes after reversal with sugammadex?
1.2 mg/kg rocuronium
What dose has been used in emergency can not intubate, cannot ventilate situations for sugammadex?
16 mg/kg
What is the minimum waiting time for readministration of rocuronium 0.6 mg/kg or vecuronium 0.1 mg/kg after reversal with sugammadex?
4 hours
To which subunits do the acetylcholine attach?
Alpha
Whose resposibility is it to ensure complete recovery from muscle relaxants?
Anesthesia provider
Anticholinesterase drugs have two sites to complement the natural substrate acetylcholine. What are they?
Anionic- binds quanternary amine Esteratic- binds to break Ach (active site)
How does temperature affect ndnmb reversal?
Antagonism is difficult when core temp reaches 32. Warm pt
Which two anticholinesterase drugs are lipid soluble?
Physostigmine and organophosphates (These have CNS effects)
Because atropine and scopolamine are uncharged, what effect do they have on pts?
Cross BBB to make pt sleepy
When did sugammadex gain approval in the US by FDA?
December 15, 2015 (you know she is gonna ask something dumb like this)
Edrophonium will be ineffective unless what recommended criteria is present?
Don't give if fewer than all four twitches (ineffective against profound ndnmb)
How do drugs affect ndnmb reversal?
Drugs may potentiate block
What is the most common type of poisoning worldwide?
Organophosphate
16 mg/kg sugammadex has been associated with increases in what important labs?
PTT PT/INR
What are the two main organophosphates a CRNA may see??
Pesticides/chemicals (migrant workers) Ecothiophate (eyedrop for glaucoma which is the only organophosphate used as med)
What is the standard of care in regards to non depolarizing blockade reversal?
Pharmacologic reversal (still give when TV is normal) (argument for is margin of safety is higher. No block desirable)
Which anticholinesterase drug is not used in reversing ndnmb because the doses are too large?
Physostigmine
