Cholinergic nervous system functions Flashcards
T/F: Cholinergic synapses in the parasympathetic nervous system are always preganglionic
False: Cholinergic synapses in the parasympathetic nervous system can be both pre- and post- ganglionic
What are the 3 sites that are targets of drug action involving the cholinergic synapses
Biosynthesis of acetylcholine, uptakes of choline and acetylcholine, release of acetylcholine
What is the enzyme, substrate, and coenzyme needed to create Acetylcholine
Choline, acetyl-CoA, choline acetyltransferase
What compound is a choline acetelytransferase inhibitor, how
NVP, imitates Acetyl-CoA and blocks binding
What are the major components for NVP to be an effective choline acetyltransferase inhibitor
napathalene ring and pyridine ring
What is the rate limiting step in acetylcholine production
uptake of choline
What protein is responsible for reuptaking choline into presynaptic nerve terminals
Carrier protein A
What is the competitive uptake inhibitor that reduces the amount of choline in presynaptic cells, how
Hemicholinium-3, it has choline like moieties that bind to the carrier protein
How many carrier proteins are inhibited by hemicholinium-3
2
T/F: Hemichlonium-3 is not acetlylated in presynaptic cell because it only blocks the carrier but never enters the cell
True
What is the false neurotransmitter the competes with choline for uptake by protein carrier A
Triethycholine (TEC)
T/F: Triethylcholine does not enter the cell
False: TEC does enter the cell and goes through the same process that choline goes through therefore competing with choline. The differece is that it is too bulky to bind to cholinergic receptors
What experimental drug prevents uptake of acetylcholine into vesicles
L-vesamicol
T/F: L-vesamicol does not bind competitively but instead allosterically to prevent acetylcholine binding
True
What antibiotic has a secondary effect that leads to less release of acetylcholine at a synapse, how
Tetracycline, complexes with calcium causing less calcium to induce release of vesicles holding acetylcholine
How does Botox (botulinum toxin) reduce the release of Acetylcholine
cleaves SNAP-25: SNAP 25 is essential for successful docking and release of acetylcholine from vesicles
What is the MOA of beta-Bungarotoxin
Causes excess release of acettylcholine that will lead to exhaustion of acetlycholine stores in the nerve terminal preventing further release of acetylcholine
What are the two types of receptors that bind acetylcholine
Muscarinic and Nicotinic
T/F: There are muscarinic and nicotinic receptors in the CNS, Autonomic, and neuromuscular regions of the nervous system
False: There are only nicotinic receptors in the neuromuscular region of the nervous system. CNS and autonomic have both
What toxin is a direct nicotinic receptor antagonist, what is the MOA
alpha-bungarotoxin, when replacing the calcium that keeps the sulfide bridges closed it also binds the free sulfide that would cause a conformational change that would open the channel
Which muscarinic receptors are excitatory, what enzymes create which 2nd messengers
M1/M3/M5, Phospholipase C, calcium
Which muscarinic receptors are inhibitory, what enzyme creates which 2nd messengers
M2/M4, Adenylate cyclase, cAMP
T/F: Ach allows for infinite rotation around the alpha carbon but the best conformation to binding to receptors is when the quaternary amine and acetyl group are at a 90 degree angle
True
What molecule could replace the nitrogen in Ach
Sulfur
What are the two key needs to bind to Ach receptor
A positively charged group, a minimum of two methyl groups on the charged functional group
What occurs if a methyl group is added to the alpha carbon of the ethylene bridge, what occurs when added to the beta carbon
selective nicotinic agonist activity, selective muscarinic agonist activity
T/F: If a methyl group is added to the alpha and beta carbons of the ethylene bride of Ach it becomes more potent to binding to Ach receptors
False: There is no activity if a methyl group is added to the beta and alpha carbon of the ethylene bridge because there is to much steric hindrance that does not allow for binding
What happens if the acetyl group is replaced by a carbamoly group in Ach, why
The agent then becomes orally active, carbomyls are more stable to hydrolysis
What are anticholinergics
Traditionally muscarinic antagonists
What is the most common muscarine antagonists
Atropine
What are chemical features that are essential for muscarinic antagonist function
A quatenary or tertiary amine bonded to at least two methyl groups (quatenary would be charged and cannot enter the BBB), an aromatic ring in the opposite directions at least 5 carbons apart
What are chemical features that are beneficial for muscarinic antagonist function
Hydrophobic ring, hydrogen bonding group
Why are anticholinergics used for people with Parkinson’s disease
Decrease the levels of Ach to achieve a close balance with dopamine levels since Parkinson’s Disease patients have less dopamine leading to tremor and rigid muscles and the anticholinergic drugs decrease levels of Ach
Where do nicotinic antagonists usually act
preganglionic synapses and neuromuscular junctions
T/F: Nicotinic antagonists in ganglia usually act as competitive or non-competitive receptor blockers
True
What is the MOA of depolorizing neuromuscular blockers type of nicotinic antagonists
Bind tightly to the Ach binding site of the nictonic Ach receptors and over stimulate the receptors causing more depolarizaition exhausting the receptor
What are two common depolarizing neuromuscular blockers
succniylcholine and decamethonium
What are key features of competitive neuromuscular junction blockers type of nicotinic antagonists
Large, charged
What do all reversible AchE inhibitors have in common
All have carbamate groups attached to aromatic rings (aryl carbamates)
What do all irreversible AchE inhibitors have in common
They are organophosphates
T/F: If the irreversible AchE inhibitor is a thiophosphate it is a prodrug that is nontoxic to mammals
True
T/F: Acetylcholine is converted back to choline before it is reuptook by pre-synaptic cells, then is converted to acetylcholine again
True
What is the aging process with regards to irreversible organophosphate poisoning, how can this be combated
Water adds to the organophosphate making the bond between the organophosphate and the drug unhydrolizable, 2-PAM interacts with the drug and site to cause hydrolysis before the aging process
