Pharm 6 - Cholinomimetics Flashcards
Describe the synthesis of acetylcholine.
Acetylcholine is synthesised from Acetyl CoA and choline via choline acetyltransferase
Why are the receptors described as nicotinic and muscarinic?
muscarinic effects can be replicated by muscarine
nicotinic effects can be replicated by nicotine
What can be given to abolish muscarinic effects?
Atropine - competitive muscarinic antagonist
State where you would find the different types of muscarinic receptors.
M1 - salivary, CNS
M2 - heart
M3 - salivary, bronchial/smooth muscle, eyes, sweat glands
What type of receptor are all muscarinic receptors?
G protein coupled receptors
What is the difference in the G-protein receptors of M1/3/5/ and M2/4?
m1/3/5/= stimulate PLC which increases IP3 and DAG
M2/4 = inhibitory
Describe the structure of nicotinic receptors.
Ligand gated ion channel
5 subunits
What are the two main types of nicotinic receptors?
Muscle and Ganglion
Muscle = 2 alpha, beta, delta, epsilon
Ganglion = 2 alpha + 3 beta
Compare the effects of acetylcholine on nicotinic receptors compared to muscarinic receptors.
weak effect on nicotinic
What are the 3 effects of muscarinic stimulation on the eye?
Contraction of the ciliary muscle (near vision)
Constriction of sphincter pupillae (circular muscle of the eye) constricts pupil
Lacrimation
What are the two effects of constriction of sphincter pupillae?
constricts the pupil
increases drainage of intraocular fluid
What is glaucoma?
Sustained raised intraocular pressure
can damage optic nerve and retina and cause blindness
Where is aqueous humour produced?
ciliary body
Describe the passage of aqueous humour through the eye.
passes anteriorly from the ciliary body into the anterior chamber
What drains aqueous humour?
Canals of Schlemm
What is the role of aqueous humour?
provides oxygen and nutrients to the cornea and iris as they don’t have blood supply as would not be transparent
What happens in angle-closure glaucoma?
angle between cornea and iris is narrowed decreasing drainage of humour through canal of Schlemm
What are the effects of giving a muscarinic agonist to people with angle closure glaucoma?
causes constriction of sphincter pupillae and opens up the angle to increase drainage of intraocular fluid
Describe the muscarinic effects on the heart.
Binding of M2 receptors causes a decrease in cAMP production
triggers a decrease in Ca2+ influx leading to decrease in cardiac output
Describe the muscarinic effects on vasculature.
triggers production of NO causing vasodilation and drop in TPR
Summarise the muscarinic effects on the cardiovascular system.
- decrease in heart rate
- decrease in cardiac output
- decrease in TPR
- decrease in blood pressure
Describe the muscarinic effects on non-vascular smooth muscle.
causes CONTRACTION
lungs - bronchoconstriction
GI - increased motility
bladder - increased bladder emptying
Describe the muscarinic effects on exocrine glands.
salivation
increased bronchial secretions
increased GI secretions
What are two types of cholinomimetic drugs?
Directly acting - muscarinic agonists
Indirectly acting - acetylcholinesterase inhibitors
What are the two types of muscarinic receptor agonists and give an example of each?
Choline Esters - bethanechol
alkaloids - pilocarpine
Describe the selectivity of pilocarpine.
Non selective muscarinic receptor agonist
stimulates all muscarinic agonists
What is pilocarpine used for?
Glaucoma (as used locally so cannot stimulate all muscarinic agonists)
State some of the side effects of pilocarpine.
Blurred vision Hypotension Sweating Respiratory difficulty GI disturbance
Describe the selectivity of bethanechol.
M3 selective agonist
What are the effects of bethanechol?
assisted bladder emptying
enhanced gastric motility
State some side effects of bethanechol.
Blurred vision Hypotension Sweating Respiratory difficulty GI disturbance Bradycardia
What are the two types of acetylcholinesterases?
Reversible
Irreversible
Give examples of reversible and irreversible acetylcholinesterases.
reversible - physostigmine, neostigmine
irreversible - ecothiopate
Where is acetylcholinesterase found?
In all cholinergic synapses
Highly selective and rapic
Where is butyrylcholinesterase found?
found in plasma and most tissues
broad specificity
State the effects of low, moderate and high doses of cholinesterase inhibitors.
low - enhances muscarinic effects
moderate - further enhances muscarinic effects + stimulates nicotinic receptors
High - depolarising block
Describe the mechanism of action of reversible anticholinesterases.
Donate carbamyl group which blocks the active site of acetylcholinesterase
carbamyl groups are removed by slow hydrolysis
Which synapses does pilocarpine primarily act on?
Postganglionic parasympathetic synapses
What is physostigmine used to treat?
Glaucoma
What type of poisoning is physostigmine used to treat?
Atropine poisoning
How does physostigmine treat atropine poisoning?
increases synaptic concentration of acetylcholine so it can outcompete atropine
What type of compounds are irreversible anticholinesterases?
Organophosphates
Describe the mechanism of action irreversible anticholinesterases.
react with enzyme active site leaving a large blocking group
blocking group is resistance to hydrolysis
What is ecothiopate used to treat?
Glaucoma
State some side effects of ecothipate.
Blurred vision Hypotension Sweating Respiratory difficulty GI disturbance Bradycardia
What type of anticholinesterase can cross the BBB?
non-polar
Describe the effects of low and high doses of anticholinesterase drugs on CNS activity.
LOW - CNS excitation
High - unconciousness, resp depression and death
State 2 anticholinesterases that are used to treat Alzheimer’s.
Donepezil
Tacrine
Describe the treatment of organophosphate poisoning.
IV atropine
What is the acute treatment of organophosphate poisoning?
Pralidoxime
