Drugs Affecting Cholinergic Neurotransmission Flashcards
Which amino acid can be converted to make ACh?
serine
Which 3 amino acids are involved in ACh metabolism?
Glu, His, Ser
Muscarinic receptor
identified by the ability of the natural product muscadine to bind to the receptor
7 transmembrane domains, 5 subtypes
all are GPCR
important in drug therapy
Nicotinic Receptor
identified by the ability of the natural product nicotine to bind to the receptor
Which 3 amino acids are involved in muscarinic receptor domains?
Asp, Thr, Tyr
General effects of muscarinic receptor activation
Diarrhea/Defecation
Urination
Miosis/ Constriction of pupil
Bradycardia (slow heart rate)
Bronchonconstriction
Excitation of CNS
Lacrimation
Salivation
Sweating
Abdominal Cramps/GI contraction
M1
PLC activation (increased IP3, DAG, Calcium, and PKC)
increase congnitive function and secretions
decrease dopamine release and locomotion
M3
PLC activation (increased IP3, DAG, Calcium, and PKC)
increased smooth muscle contraction and salivary gland secretion
M5
PLC activation (increased IP3, DAG, Calcium, and PKC)
facilitates dopamine release; augments drug seeking behavior and reward
M2
Inhibition of adenylyl cyclades and voltage gated calcium channels
decreased heart rate
increased smooth muscle contraction
M4
Inhibition of adenylyl cyclades and voltage gated calcium channels
facilitates dopamine release, inhibits transmitter release in the CNS
Which receptors activate phospholipase C
odd numbered/ G alpha Q
Which receptors are inhibitory and decrease cAMP
Gi/even numbered receptors
Which receptors decrease voltage gated calcium channels?
Go / even numbered receptors
What are the issues with using ACh as a drug?
non-selective
minimal bioavailability
The positive nitrogen on ACh and muscarine is good for forming ionic bonds with receptors but poor for ?
absorption
Methacholine
used for diagnostic tests
selective for muscarinic vs nicotinic receptors
equipotent with ACh but decreased rate of hydrolysis
Carbachol
isosteric change to ACH
carbamate is not as easily hydrolyzed as an ester
used in ophthalmics
Bethanechol
has carbamate and methyl group added on to ACh
used orally for urinary retention
Pilocarpine
act as muscarinic agonist
natural alkaloid
used opthalmically and orally for dry mouth
Cevimeline
synthetic muscarinic agonist
used orally for dry mouth
Alzheimer’s disease
ACh deficiency; progressive degeneration of cholinergic neurons
AChE inhibitors
indirect ACh agonists
will produce a non specific response
useful for glaucoma treatment- miosis, myasthenia gravis- incr ACh duration of action, Alzheimer’s- slow decline of memory, and to reverse mydriasis or effects of nondepolarizing neuromuscular blocking agents
Myasthenia gravis
chronic autoimmune neuromuscular disorder
fluctuation weakness of voluntary muscle groups
In pseudoirreversible inhibitors a carbamate is left on a Ser, what is the speed of hydrolysis ?
slow
Aryl Carbamates
have increased affinity for AChE, making them better inhibitors
includes physostigmine, neostigmine, pyridostigmine, and rivastigmine
Order of rate of carbamylation of AChE
carbamic acid esters>methylcarbamic acid esters>dimethylcarbamic acid esters> methyl, ethyl
Neostigmine and pyridostigmine treat
myasthenia gravis
physostigmine treats
open-angle glaucoma
rivastigmine treats
alzheimer’s
Donepezil, Galantamine, and Ambenonium Chloride are?
Non-carbamoylating AChE inhibitors
Can quarternary salts cross the blood brain barrier?
no
A slower carbamylation leads to slower?
regeneration of AChE
Carbamylating agents may lead to ?
increased cholinergic effects
Irreversible AChE inhibitors
used in as low of a dose as possible
used in a lot of insecticides
Symptoms of Organophosphate toxicity
increased GI peristalsis
miosis, loss of ocular accomodation, ocular pain
rhinorrhea
chest tightness and wheezing
increased lacrimation, salivation, and sweating
bradycardia and hypotension
confusion
convulsions
weakness, muscle paralysis, respiratory paralysis
What combination can reverse anti-AChE toxicities ?
atropine and pralidoxime
Pralidoxime Chloride
antidote to reverse muscle paralysis resulting from organophosphate AChE peticide poisoning
it’s oxime has a higher affinity for phosphate as opposed to a hydroxyl group
Muscarinic receptor antagonists block?
muscarinic actions of ACh
DUMBELLS
What are the 3 main stimulators of gastric acid release?
ACh, histamine, and gastrin
What are the first line drugs for treatment of COPD?
ipratropium and tiotropium
Alkaloid
nitrogen containing compound that is isolated from natural sources and possesses a pharmacological action
Ing’s Rule of 5
5-6: Agonist
7-8: Partial Agonist
>9: Antagonist
When an active site is occupied and the auxiliary site is not used, then the receptor exists in a conformation that produces an?
agonist effect
When both active and auxiliary sets are occupied what kind of effect is produced?
Antagonist effect
Ipratropium, Tiotropium, and Aclidinium Bromide are all?
Bronchodilators
quaternary ammonium anticholinergic agents
ACh action at M1 and M3 receptors causes bronchoxxx?
bronchoconstriction
Amino Alcohol Esters (Synthetic Antimuscarinic Drugs)
glyopyrroolate, propantheline, flavoxate, dicyclomine, cyclopentolate, and mepenzolate bromide
Amino Ethers (Synthetic Antimuscarinic Drugs)
diphenhydramine, bentropine, and orphenadrine
Amino Alcohols (Synthetic Antimuscarinic Drugs)
procyclidine, trihexyphenidyl, biperiden
Tropicamide and Tolterodine are ?
Synthetic Antimuscarinic Drugs
All synthetic anti muscarinic drugs are selective for?
the muscarine receptor
Where are nicotinic receptors located?
sympathetic and parasympathetic ganglia
How many ACh binding site are on the extracellular domain of each receptor molecule?
2
What kind of antagonists are nicotinic antagonists?
competitive
How can you reverse nicotinic antagonists ?
by administering an AChE inhibitor
Skeletal Neuromuscular Blocking Agent
used in anesthesia
nicotinic antagonist
Ganglion is blocking agents
orphan drug for treatment of nicotine- responsive psychiatric disorders and nicotine and codein addiction
nicotinic antagonist
What structural features do synthetic neuromuscular blocking drugs need
2 quaternary ammonium groups/ tertiary amines spread 10-12 atoms apart
Succinylcholine Chloride
ultrashort duration; depolarizing
cannot be reversed by neostigmine
used for rapid induction of muscle relaxation
administered IV
Pancuronium Bromide
Long duration; competitive
don’t use in patients with CAD
Vecuronium Bromide
intermediate duration; competitive
Rocuronium Bromide
intermediate duration; competitive
Atacurium Besylate
intermediate duration; competitive
depends on renal elimination
Mivacurium Chloride
Short duration; competitive
Pancuronium Bromide, Vecuronium Bromide, and Rocuronium Bromide are all?
steroid based blocking drugs
Atacurium Beslyate and Mivacurium Chloride are ?
tetrahydroisoquinoline based blocking drugs
Adverse effects of neuromuscular blockers
hypotension, bronchospasm, cardiac disturbances, twitching before relaxation, histamine release
