Acetylcholine and Parasympathetic System Flashcards
Name the two compounds from which ACh is synthesized. Also state which one is the precursor.
Precursor, Choline (from diet) and acetyl-CoA
Name the enzyme that converts choline and acetyl-CoA to ACh
Acetyltransferase
From what is choline derived? And where
Diet, liver
Which transporter will transport choline into the nerve terminal?
High affinity Na-choline co-transporter
Which transport inhibitor can reduce the synthesis of Acetycholine?
Hemicholinium, a neuronal choline transporter inhibitor
Where is ACh stored after being synthesized?
ACh is transported by vesicle transporter to be stored in vesicles
Which drug can inhibit the vesicular transporter responsible for transporting ACh into vesicles?
Vesamicol
By which mechanism is ACh released into the synaptic cleft?
Ca- dependent exocytosis
How is the action of ACh in the synaptic cleft terminated?
The action of acetylcholine in the synapse is normally terminated by metabolism to acetate and choline by the enzyme acetylcholinesterase in the synaptic cleft.
What is the result when cholinesterase enzymes are blocked/inhibited?
Blockade of cholinesterase enzymes result in increased autonomic activity, primarily cholinergic activity. Increased effects at postganglionic nerve terminal with increased stimulation of muscarinic receptors, enhancing synaptic cholinergic activity, causes excessive salivation, bradycardia, bronchospasm and hypotension. Increasing NMJ activity causes muscle fasciculation and twitching and may result in a depolarisation block and paralysis
Name two receptors of ACh on postsynaptic neurons.
Nicotinic receptors
Muscarinic receptor
Where do you find nicotinic receptors?
Ganglia
Adrenal gland
Neuromuscular junction
Where do you find muscarinic receptors?
Cardiac
Smooth muscle
Exocrine glands
Which acetylcholinesterase inhibitor is commonly used?
Neostigmine
Name the Effects of blocking ACh vesicular release.
Inhibition of sweating, giving symptoms of a dry, warm skin
Inhibition of salivation with symptoms of dry mouth
Pupillary dilatation
Inhibition of vesicular release at the neuromuscular junction would lead to muscle paralysis
Which drugs results in Inhibition of vesicular release of ACh at the neuromuscular junction?
Streptomycin , neomycin
which poison causes parasympathetic paralysis with symptoms of a dry mouth and blurring of vision
Botulinum
Which venom causes parasympathetic paralysis with symptoms of a dry mouth and blurring of vision
Beta-bungarotoxin
What type of receptor are Nicotinic receptors?
ligand-gated ion channels
What type of receptor are Muscarinic receptors?
G-protein coupled receptors
From which cranial nerves does parasympathetic preganglionic fibres originate?
Cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus)
From which spinal cord region does preganglionic parasympathetic fibres arise?
sacral region (S2 to S4) of the spinal cord
How many preganglionic parasympathetic fibres does the vagus nerve account for?
90%
Which areas of the body does the postganglionic neuron from the vagus nerve innervate?
most of the organs in the thoracic
and abdominal cavity.
Name the two groups of cholinergic drugs
Direct acting
Indirect acting - anticholinesterase agents
Name the two groups of direct acting cholinergic drugs
Choline Esters
Natural alkaloids
Name the two groups of anti-cholinesterase agents
Irreversible and reversible
Name two examples of choline esters
Acetylcholine
Bethanechol
What is the prototype for direct acting cholinergic drugs?
Acetylcholine
What is the prototype for indirect acting anticholinesterase inhibitors?
Neostigmine
Does bethanechol (quarternary compound) penetrate the BBB?
No
Why is bethanechol’s action more prolonged than that of ACh?
It is not hydrolysed by cholinesterase
Give an example of natural alkaloids
Pilocarpine
In which occular disease is pilocarpine prefered?
Closed-angle glaucoma
The commonly used anticholinesterases are quaternary compounds that…
…do not pass the blood-brain barrier and have negligible central effects.
MOA of acetylcholinesterase
Acetylcholine binds to the active site of the esterase and is hydrolysed, producing free choline and acetylated enzyme. In second step, the covalent acetyl-enzyme bond split with the addition of water.
Why is pilocarpine effective in closed-angle glaucoma?
Pilocarpine reduce IOP by contracting the ciliary muscle. This pulls the sclera spur and result in the trabecular meshwork being stretched and separated. The fluid pathways are opened up and aqueous outflow is increased
All parasympathomimetic causes…
miosis (excessive pupillary constriction)
Name two drugs that reduce IOP by decreasing aqueous secretion
Timolol
Brimonidine
How does timolol decrease aqueous secretion?
Beta blocker, it blocks B-2 receptors on the ciliary processes and reduce aqueous production. They may block vessels supplying the ciliary processes. The resulting vasoconstriction produces reduced ultrafiltration and aqueous formation.
How does brimonidine decrease aqueous secretion?
Alpha 2 adrenoceptor agonists, they decrease aqueous by stimulating alpha 2 adrenoceptors on the adrenergic nerve terminal innervating the ciliary body
What is Myasthenia Gravis
Characterized by progressive weakening of skeletal muscles. It preferentially affects women and can be lethal if untreated.
Symptoms are caused by an autoimmune-induced decrease (70-90%) in the number of nAChRs at the NMJ. Ptosis and weakness of smile are common early signs.
Which drug is diagnostic in early stages of Myasthenia Gravis?
Edrophonium (acetylcholinesterase inhibitor)
Can edrophonium be used as therapy for myasthenia gravis?
Yes, but neostigmine is preferred
Name the adverse effects of AChE inhibitors.
The same as sx of ACh excess - DUMBELS: diarrhea, urination, miosis, bronchoconstriction, excitation, lacrimation (flow of tears), salivation and sweating.
Name the two drugs that can be used for Myasthenia Gravis due to their higher affinity for the NMJ than the rest of the ANS
Neostigmine
Pyridostigmine
Give four examples of reversible anticholinesterase agents
Neostigmine
Physostigmine (eserine)
Pyridostigmine
Edrophonium
Explain MOA of edrophonium
It binds by electrostatic forces to the active site of the enzyme. It does not form covalent bonds with the enzyme
Name the two groups of irreversible anticholinesterase agents
Organo Phosphorus Compounds
Carbamates
Name the three groups of anticholinergic drugs
Antimuscarinic
Anti-nicotinic
Cholinesterase regenerators
Give an example of a non-selective antimuscarinic drug
Atropine
Give an example of a cholinesterase regenerator drug and name its class
Pralidoxime - Oximes
Name the different effects of the parasympathetic nervous system
Constricts pupils Stimulates flow of saliva Constricts bronchi Slows heartbeat Stimulates peristalsis and secretion in stomach Stimulates bile release Contracts bladder
Atropine MOA, uses in therapeutics, effects/side-effects
Tertiary amine with competitive binding to muscarinic receptors
Treatment of organophosphate poisoning
Antispasmodic, antisecretory, mydriasis and cycloplegia
Glycopyrrolate - MOA, uses
Antimuscarinic/bronchodilator Quaternary amine,
Used for reversal of neuromuscular blockade
Preoperative medication
Ophthalmology to produce mydriasis and cycloplegia
Give 5 examples of antimuscarinic drugs
Atropine Scopolamine Glycopyrrolate Oxybutynin (antispasmodic, urge incontinence, Post operative urinary spasms) Imipramine (reduces incontinence)
Ipratropium bromide - MOA, uses
anticholinergic/bronchodilator/nasal agent
asthma/COPD when not controlled by LABA, corticosteroids, spacer
Give an example of nicotinic agonist
succinylcholine - stimulates skeletal muscle contraction
Give an example of a nicotinic antagonist
Pancuronium - inhibits skeletal muscle contraction
