m and m 12 Cholinesterase Inhibitors & Other Pharmacologic Antagonists Flashcards
Where his acetylcholine made? What his name the enzyme in order the 2 moieties used to make acetylcholine?
Acetylcholine is made in the nerve terminal
Components are acetylcoA and choline
Enzyme is choline-acetyltransferase
What enzyme metabolizes acetylcholine? What are the breakdown products?
Acetylcholine esterase
Choline and acetate
What parts of the sympathetic NS use acetylcholine as a neurotransmitter?
Adrenal medulla
Sweat glands
Sympathetic ganglions
Where are muscarinic receptors found (3)? What about nicotinic?
Muscarinic - bronchial smooth muscle, sinoatrial node, salivary glands
Nicotinic - skeletal muscle
What receptors to bethanechol, methacholine and carbachol target?
Methacholine and bethanechol target muscarinic receptors, carbachol targets both muscarinic and nicotinic receptors
Name a specific use of methacholine, bethanechol and carbachol (1 each)?
Methacholine - asthma provocation test
Bethanechol - bladder atony
Carbachol - topically for wide angle glaucoma
true/false - primary goal in reversing neuromuscular blockade is maximizing muscarinic transmission while minimizing nicotinic transmission.
False - other way around
What are the 4 mechanisms / components of “spontaneous reversal” of non-depolarizing neuromuscular block? What is the other means of reversal?
Gradual Diffusion Redistribution Metabolism Excretion Pharmacological reversal
Cholinesterase inhibitors block acetylcholine by binding reversibly. What types of bonds do edrophonium, pyridostigmine and neostigmine form?
Edrophonium - electrostatic bonds, short lived
Pyridostigmine and neostigmine - covalent bonds, longer lived bonds
What differentiates organophosphates from edrophonium, pyridostigmine and neostigmine with regards to the types of binds formed with cholinesterase?
Organophosphates form stable irreversible bonds
Beyond acetylcholinesterase inhibition, some cholinesterase blockers may reverse neuromuscular blockade in other ways. Edrophonium for example does what?
Edrophonium may enhance the release of acetylcholine
Beyond acetylcholinesterase inhibition, some cholinesterase blockers may reverse neuromuscular blockade in other ways. Neostigmine for example does what?
Neostigmine may have weak agonist effects at nicotinic receptors
What is the effect of excess acetylcholinesterase inhibitors?
- Paradoxically potentiate a non-depolarizing neuromuscular block
- Prolong depolarization blockade by succinylcholine
Edrophonium, pyridostigmine and neostigmine. Which one(s) blocks pseudocholinesterase at higher doses?
Pyridostigmine and neostigmine.
True or false - large doses of neostigmine can cause weak depolarizing neuromuscular blockade?
True
What is the effect of increased cholinergic transmission on the CV system?
Increased bradycardia that can become sinus arrest
What is the effect of increased cholinergic transmission on the Respiratory system?
Will cause bronchospasm and increased secretions
What acetylcholinesterase inhibitor will cross the blood brain barrier? What might be seen on EEG? Mechanism? Significance for anesthetics?
- Physostigmine
- Diffuse activation of the EEG by stimulating muscarinic and nicotinic receptors in the CNS
- General anesthetics may work by blocking nicotinic acetylcholine receptors in the CNS. If used (it is not), physostigmine may alter the effects of general anesthetics
What is the effect of increased cholinergic transmission on the GI system?
Increases peristalsis
Increases glandular secretions
It is hard/impossible to immediately reverse a block so intense that there is no response to tetanic peripheral nerve stimulation. What should be seen before reversal is attempted?
At least the first twitch of the train of four.
The post tetanic count (number of palpable twitches after tetanus) correlates with _.
The time of return of the first twitch of the train of four, which signifies the ability to reverse intense paralysis
Arrange in order of sensitivity for adequacy of reversal. Tidal volume, sustained head lift, inspiratory force, vital capacity
Sustain head lift > inspiratory force > vital capacity > tidal volume
What are the 2 moieties that make up neostigmine?
Carbamate group and a quaternary ammonium (latter makes lipid insoluble, can’t cross BBB)
What is the ratio of glycopyrrolate used for each mg of neostigmine?
0.2 mg glyco for each 1 mg of neostigmine
In what group of patients is duration of action prolonged for neostigmine?
Geriatric patients
Which anticholinergic agent is associated with more tachycardia, atropine or glycopyrrolate?
Atropine is assoc with more tachycardia
True of false, neostigmine can be used to treat myasthenia gravis, paralytic ileus and bladder atony.
True
What is the difference structurally between neostigmine and pyridostigmine?
Quaternary group of pyridostigmine is incorporated into the phenol ring.
How strong is pyridostigmine relative to neostigmine?
Pyridostigmine is only 20% as strong as neostigmine
How do the onset of action and duration of action of neostigmine and pyridostigmine compare?
Neostigmine onset (5 mins), duration (1 hour) Pyridostigmine onset (10-15 minutes), duration (2 hr)
What is the preferred anticholinergic for pyridostigmine and why?
Glycopyrolate - because its slower onset matches that of pyridostigmine (compared to atropine)
What is the reason, structurally, that edrophonium doesn’t bind covalently to acetylcholinesterase?
It lacks a carbamate group
What is the potency of edrophonium relative to neostigmine?
It is less than 10% as potent as neostigmine
How does onset of action of edrophonium compare to neostigmine? How can you prolong the duration of action of edrophonium?
Edrophonium onset is 1-2 mins, compared to 5 for neostigmine. Can get longer duration of action for edrophonium by using higher doses
What is the preferred anticholinergic for Edrophonium and why?
Atropine, because it has the same fast onset of action
What make physostigmine structurally different from the other cholinesterase inhibitors?
Has carbamate like the rest but no quaternary amine, making it able to cross the BBB
Why is physostigmine not useful for reversing neusomuscular blockade? What is it used for instead?
It will cross BBB
Used instead for the treatment of central anticholinergic toxicity from atropine or scopolamine, can also reverse CNS depression and delirium from benzos and volatile anesthetics
Which acetylcholinesterase blocker can be used for post-op shivering? What is the mechanism of this agent being able to block morphine induce respiratory depression?
Physostigmine
Blocks morphine induced respiratory depression as presumed mechanism is morphine reduces acetylcholine signaling in the brain
What is the mechanism of inactivation of physostigmine?
Almost completely metabolized by plasma esterases, making renal excretion unimportant (unlike the other acetylcholinesterase blockers)
You want to reverse CNS effects of physostigmine. Glycopyrrolate or atropine and why?
Atropine, because glycopyrrolate doesn’t cross the BBB
What electrolyte disturbances potentiate neuromuscular blockade?
Hypermagnesemia
Hypocalcemia
Hypokalemia
Respiratory acidosis
Which potentiates neuromuscular block, hyperthermia or hypothermia?
Hypothermia
What are the class of neuromuscular blockers that can be reversed by sugammadex? What are 3 examples?
Aminosteroids
Rocuronium, pancuronium, vecuronium
What is the structural basis for sugammadex reversal of neuromuscular blockers?
Traps the aminosteroid in the hydrophobic cavity in a 1:1 ratio, restraining its ability to interact with receptors
What is the time line of recovery of a rocuronium block by sugammadex?
Can reverse a rocuronium block to 0.9 TOF ratio in 2 minutes
L-cysteine is able to reverse neuromuscular block by what class of neuromuscular blockers? What is the mechanism?
Reverses block by fumarates (e.g. gantacurium)
Mechanism is it binds and forms less active degradation products (adducts)
