9-Cholinergic Pathway Flashcards
Why are cholinergic and anticholinergic drugs limited?
They’re limited by the ubiquitous and complicated nature of cholinergic pathways- it’s hard to achieve desired therapeutic effects without adverse effects.
What is the enzyme that combines Acetyl-CoA and Choline to form Ach?
CAT (choline acetyltransferase)
What is the transporter that brings the choline molecule into the cytoplasm?
NCS (Na-Choline symporter)
What drug blocks the NCS transporter?
Hemicholinium
After Ach is synthesized, where is it stored?
Vesicles
What is the transporter that brings the Ach into the vesicle?
ATPase antiporter (takes H out)
What drug blocks the ATPase antiporter on the vesicle, thus not allowing Ach to enter vesicles to be released?
Vesamicol
An increase in what ion causes the vesicles with Ach to be released?
Ca++
What are the proteins called on the axon terminal that the vesicle binds to for it’s exocytosis?
SNARE proteins
What drug blocks SNARE proteins?
Botulinum toxin (Botox!)
After Ach does its thanggg on the postsynpatic cell, what enzyme degrades it?
Acetylcholinesterase
What is an example of a drug that inhibits acetylcholinesterase, thus increasing [Ach] in the synapse?
Physostigmine
Are nicotinic Ach receptors ligand or G-protein coupled?
Ligand
Where are nicotinic(m) Ach receptors?
Skeletal muscle
Are muscarinic Ach receptors ligand or G-protein coupled?
G-protein coupled
Are M1 receptors excitatory or inhibitory?
Excitatory
Where are M1 receptors?
Autonomic ganglia, CNS
Where are M2 receptors?
heart
Are M2 receptors excitatory or inhibitory?
Inhibitory
What is the mechanism of action of M2 receptors?
Gi coupled (inhibits AC)
Where are M3 receptors?
Smooth muscle
Are M3 receptors excitatory or inhbitory?
Excitatory
What is the mechanism of action of M1 and M3 receptors?
Gq coupled (PLC/IP3/DAG)
Where are nicotinic(n) receptors?
CNS postganglionic cell body and dendrites
How many Ach molecules are required to open the NmAchR?
2
How do the subunits of the NmAchR differ?
they each have 2 alpha, 1 beta, 1 delta, and either 1 gamma or epsilon.
What is the function of butyrylcholinesterase (BuChE)?
It’s a nonspecific cholinesterase which is less efficient than AchE.
What is the self-regulatory, + feedback loop of Ach release at the NMJ?
On the presynaptic terminal, there are receptors that bind Ach, so when Ach is released, they also bind to these receptors that trigger more Ach release. This makes sure there is a lot of Ach released into the cleft for muscle contraction.
What drug blocks the Ach + feedback receptors, thus reducing the [Ach] in the synapse?
Hexamethonium
How does the direct acting cholinergic drugs work to increase the Muscarinic receptor activity?
They cause the release of Ach from the presynaptic neuron to bind to the muscarinic receptors
How does indirect acting cholinergic drugs work to increase Ach in the synapse?
They inhibit AchE, which prevents the breakdown of Ach in the synapse.
How does atropine work?
Blocks all muscarinic receptors
What is an EPSP?
It’s a depolarization of the postsynaptic membrane, usually by the opening of NmAchR’s
Does an EPSP always result in an action potential down the sarcolemma?
No. Typically you need a handful of EPSP’s to reach threshold and cause an action potential
What is an IPSP?
It is the hyperpolarization of the postsynaptic membrane, which takes it further away from the threshold
What receptors modulate slow EPSP’s?
M1AchR’s
What is a good acronym for the effects of cholinergic activation?
DUMBBELSS
What does DUMBBELSS stand for?
diarrhea, urination, miosis, bradycardia, bronchoconstriction, excitation (as of muscle in the form of fasciculations and CNS), lacrimation, salivation, and sweating
What brain process is Ach key in while you’re awake?
Forming new memories
What is Ach key in while you’re asleep?
consolidating the new memories. Maybe this is why it’s good to be not stressed to learn better while you’re awake, and to get a good night sleep so you store all those formed memories. ??? DSP > all ???
Real quick: What did the ghost say to the bees?
boobies
What role does Ach have in cognitive function?
It’s essential for it- a decrease in Ach is correlated with dementia and whatnot.
Hemicholinium- mechanism of action (MOA)
blocks the high-affinity transporter for choline and thereby prevents the uptake of choline required for ACh synthesis.
Vesamicol- MOA
blocks the ACh-H+ antiporter that is used to transport ACh into vesicles.
Botulinum toxin- MOA
degrades synaptobrevin and thus prevents synaptic vesicle fusion with the axon terminal (presynaptic) membrane
Edrophonium- use
short-acting (2–10 minutes); rapid onset of action makes edrophonium useful for diagnosis of muscle weakness
Edrophonium- clinical significance(CS)
Diagnosis of myasthenia gravis, Eaton-Lambert syndrome, and disorders resulting in muscle weakness
Neostigmine/pyridostigmine- use
For chronic treatment of myasthenia gravis, longer-acting cholinesterase inhibitors, also has direct cholinergic agonist effect at NM receptors OUTSIDE THE CNS
Neostigmine/pyridostigmine- CS
Urinary or gastrointestinal motility agent, glaucoma, neuromuscular junction diseases such as myasthenia gravis
Physostigmine- Use
Used in the treatment of anticholinergic drug overdoses in the CNS, bc it can cross BBB
Physostigmine- CS
Increases intestinal and bladder motility Produces miosis and spasm of accommodation and lowers intra-ocular pressure topically in eye Used in the treatment of anticholinergic drug overdoses Atropine, phenothiazines, tricyclic antidepressants
Edrophonium, Neostigmine,Pyridostigmine,Physostigmine- MOA
They are indirect cholinergics- block AchE which increases [Ach] in the synapse
Does physostigmine enter the CNS?
Yes
Diisopropyl fluorophosphates- use
An organophosphate compound used as an insecticide, as a substrate for the production of organophosphate chemical weapons (nerve gases), and formerly as a topical miotic medication in ophthalmology
Diisopropyl fluorophosphates- MOA
binds irreversibly to AchE, creating massive parasympathetic responses.
What is aging, in reference to the organophosphates?
Aging: the enzyme–organophosphate complex is subject to a process known as aging, in which oxygen–phosphorus bonds within the inhibitor are broken spontaneously in favor of stronger bonds between the enzyme and the inhibitor. Once aging occurs, the duration of AChE inhibition is increased even further. Thus, organophosphate inhibition is essentially irreversible, and the body must synthesize new AChE molecules to restore AChE activity.
What drug can be administered before aging has occurred to recover enzymatic function from the inhibited AChE?
Pralidoxime (PAM)
Tacrine,Donepezil,Rivastigmine,Galantamine- use
-Tacrine, donepezil, rivastigmine, and galantamine produce modest symptomatic benefits in Alzheimer’s disease -Rivastigmine affects both acetylcholinesterase and butyrylcholinesterase by forming a carbamoylate complex with the enzymes -Galantamine also acts as a non-potentiating ligand of nicotinic receptors
Tacrine,Donepezil,Rivastigmine,Galantamine- CS
Mild to moderate Alzheimer’s disease Dementia
Methacholine- MOA
Muscarinic agonist
Methacholine- use
Diagnosis of asthma
Methacholine- structure
Methacholine is highly resistant to acetylcholinesterase; it is relatively selective for cardiovascular muscarinic cholinergic receptors Choline ester
Carbechol- MOA
Muscarinic agonist
Carbechol- CS
has enhanced nicotinic action relative to other choline esters; carbachol cannot be used systemically because of its unpredictable nicotinic action at autonomic ganglia; topical application of carbachol to the cornea of the eye results in both pupillary constriction (miosis) and decreased intraocular pressure
Carbechol- use
Glaucoma
Carbechol- structure
Choline ester
Benthanechol- CS
almost completely selective for muscarinic receptors
Benthanechol- use
Stimulates atonic bladder Treats neurogenic atony and megacolon
Benthanechol- structure
Structurally related to ACh Choline ester
What are the alkaloid muscarinic agonists?
Muscarine Pilocarpine Cevimeline
Pilocarpine,Cevimeline- use
Xerostomia in Sjogren’s syndrome
Succinylcholine- MOA
Stimulate opening of nicotinic ACh receptor channel and produce depolarization of the cell membrane; succinylcholine persists at the neuroeffector junction and activates the nicotinic receptor channels continuously, which results in inactivation of voltage-gated sodium channels so that they cannot open to support further action potentials (sometimes called “depolarizing blockade”)
Succinylcholine- use
Short duration of action makes succinylcholine drug of choice for paralysis during intubation. Causes transient fasciculations
Atropine- MOA
Muscarinic receptor antagonist
Atropine- Use
Anticholinesterase overdose Acute, symptomatic bradycardia Premedication for anesthetic procedure Excessive salivation and mucus secretion during surgery Antidote to mushroom poisoning
Scopolamine- MOA
Muscarinic receptor antagonist
Scopolamine- use
Motion sickness Nausea and vomiting
Ipratropium/Tiotropium- Use
COPD
Ipratropium/Tiotropium- MOA
Muscarinic receptor antagonist
What are the antimuscarinic drugs that treat incontenence?
Oxybutynin Tolterodine Fesoterodine Darifenacin Solifenacin
What are the antimuscarinic drugs that treat parkinsons?
Biperiden Benztropin Trihexylphenidyl
Tubocurare- MOA
NmAchR antagonist
Tubocurare- CS
long acting, Nondepolarizing blocking agents have variable adverse effects associated with ganglionic blockade, which can be reversed by administration of AChE inhibitors
Tubocurare- use
Induction of neuromuscular blockade in surgery. Intubation
Mecamylamine and Trimethaphan- MOA
NmAchR antagonist
Mecamylamine and Trimethaphan- CS
Mecamylamine and trimethaphan are administered when ganglionic blockade is desired; these drugs lower blood pressure while simultaneously blunting the sympathetic reflexes that would normally cause a deleterious rise in pressure at the site of the tear in cases of aortic dissection
Mecamylamine and Trimethaphan- use
Hypertension in patients with acute aortic dissection
Case Scenario:
Patient presents to ER with the following symptoms: BP 70/30, HR 40, RR 8, pupils constricted, vomiting, sweating and bronchoconstriction. Patient’s friend states he has been hiking and tried some funky mushrooms. What is the drug of choice?
A. Physostigmine
B. Atropine
C. Benthanechol
D. Botulinum toxin
B. Atropine
Patient is experiencing DUMBBELSS from muscarine exposure. Atropine, a potent antimuscarinic drug, will counter his symptoms.
What is the treatment for smoking?
Varenicline (chantix)
Case Scenario:
Farmer presents to ER with the following symptoms: BP 70/30, HR 40, RR 8, pupils constricted, vomiting, sweating and bronchoconstriction. Patient’s friend states he has been using a new form of insecticide without mask protection. What is the drug of choice?
A. Neostigmine
B. Carbechol
C. Pralidoxime (PAM)
D. Atropine
E. C and D
E. Both atropine and pralidoxime
Symptoms are from exposure to a organophosphate, which irreveribly binds to AchE, thus increasing [Ach] in the NMJ synapse. PAM will prevent the aging process (talked about earlier) and atropine will counter his current DUMBBELSS symptoms.
