Cholinomimetics Flashcards
Describe the synthesis of acetylcholine.
Acetylcholine is synthesised from Acetyl CoA and choline via choline acetyltransferase (CAT)
Why are the receptors described as nicotinic and muscarinic?
Muscarinic effects are those that can be replicated by muscarine + abolished by atropine. Correspond to parasympathetic stimulation.
Nicotinic effects are those that an be replicated by nicotine
State where you would find the different types of muscarinic receptor.
M1: salivary glands, CNS, stomach
M2: heart
M3: salivary glands, bronchial/ visceral smooth muscle, eyes, + sweat glands
M4 and M5 are found in the CNS
NOTE: generally excitatory except for on the heart
What type of receptor are all muscarinic receptors?
G-protein coupled receptors
What is the difference in the G-protein receptors of M1, M3 and M5 compared to M2 and M4?
M1, M3 and M5 = Gq protein linked receptors: they stimulate PLC which increases IP3 and DAG
M2 and M4 = Gi protein linked receptors (inhibitory) – they decrease the production of cAMP
Describe the structure of nicotinic receptors. What determines its ligand binding properties?
Ligand gated ion channels- consist of 5 subunits (alpha, beta, gamma, delta or epsilon)
Combination of subunits determines ligand binding properties.
What are the 2 main types of nicotinic receptor? Describe their subunit composition.
Muscle = 2 alpha + beta + delta + epsilon Ganglion = 2 alpha + 3 beta
How do the effects of acetylcholine on nicotinic receptors compare to its effects on muscarinic receptors?
Effects of ACh are relatively weak on nicotinic compared to muscarinic
What 3 effects does muscarinic stimulation have on the eye?
Contraction of the ciliary muscle (accommodates near vision)
Constriction of sphincter pupillae (circular muscle of iris) – this constricts the pupil + increases drainage of intraocular fluid
Lacrimation
What is glaucoma?
Sustained raised intraocular pressure
Can cause damage to the optic nerves + retina
Can lead to blindness
Where is aqueous humour produced? Describe its passage through the eye.
Capillaries in the ciliary body produce aqueous humour
which flows anteriorly into the anterior chamber and is then drained through the canals of Schlemm into the venous system
What is the role of aqueous humour?
Provides oxygen and nutrients to the cornea and lens because they don’t have a blood supply
What happens in Angle-closure glaucoma?
Angle between cornea + iris is narrowed, which decreases the drainage of intraocular fluid through the canals of Schlemm, thus intraocular pressure increases
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 the drainage of intraocular fluid
Describe the muscarinic effects on the heart.
Binding of ACh to M2 receptors causes a decrease in cAMP production
This triggers a decrease in Ca2+ influx, which leads to a decrease in CO
It also triggers an increase in K+ efflux, which leads to a decrease in HR
Describe the muscarinic effects on the vasculature.
No direct parasympathetic innervation of blood vessels
However, there are muscarinic receptors on the endothelial cells
ACh stimulates production of NO from the endothelial cells, which causes vasodilation and a decrease in TPR and BP
Summarise the muscarinic effects on the cardiovascular system.
Decrease in HR
Decrease in CO (due to decreased atrial contraction)
Decrease in TPR (due to vasodilation)
Decrease in BP
Describe the muscarinic effects on non-vascular smooth muscle.
Opposite of muscarinic effects on vascular smooth muscle
It causes CONTRACTION of non-vascular smooth muscle
Lungs = bronchoconstriction (difficulty breathing)
GI tract = increased motility (GI pain)
Bladder = increased bladder emptying
Describe the muscarinic effects on exocrine glands.
Salivation
Increased bronchial secretions
Increased GI secretions (including gastric HCl production)
Increased sweating (sympathetic-mediated)
What are the 2 types of cholinomimetic drug?
Directly Acting: muscarinic agonists
Indirectly Acting: acetylcholinesterase inhibitors -> increase the synaptic concentration of ACh
State 2 types of muscarinic receptor agonists and give an example of each.
Choline Esters e.g. Bethanechol
Alkaloids e.g. Pilocarpine
Describe the selectivity of pilocarpine.
Non-selective muscarinic receptor agonist
It stimulates ALL muscarinic receptors
What is pilocarpine used to treat?
Glaucoma (stimulates muscarinic receptors of iris, flattening iris + improving drainage)
State 5 side-effects of pilocarpine.
Blurred vision Hypotension Sweating Respiratory difficulty GI disturbance and pain
Describe the selectivity of bethanechol.
M3 selective agonist
What are the effects of bethanechol?
Assist bladder emptying
Enhanced gastric motility
State some side-effects of bethanechol.
Same as pilocarpine + bradycardia
Higher incidence of side effects as systemic (oral)
What is the half-life of pilocarpine and bethanechol?
3-4 hours
What are the 2 types of anticholinesterase? Give examples of each.
Reversible e.g. physostigmine, neostigmine, donepezil
Irreversible e.g. ecothiopate, dyflos, sarin
What are the 2 types of cholinesterase? What do they do?
Acetylcholinesterase
Butyrylcholinesterase
Metabolise ACh to choline and acetate
Where is acetylcholinesterase found? Describe its properties.
Found in ALL cholinergic synapses
Has very RAPID action and it is HIGHLY SELECTIVE for ACh
Where is butyrylcholinesterase found? Describe its properties
Found in plasma and most tissues but NOT cholinergic synapses
Has a broad substrate specificity – it hydrolyses other esters e.g. suxamethonium
Is principle reason for low plasma ACh
It shows genetic variation
State the effects of low, moderate and high doses of cholinesterase inhibitors.
LOW: enhances muscarinic effects
MODERATE: further enhances muscarinic effects + increases transmission at ALL autonomic ganglia (nAChRs)
HIGH: depolarising block at autonomic ganglia + NMJ (nicotinic receptors get overstimulated so they shut down)
Describe the mechanism of action of reversible anticholinesterases.
Compete with ACh for active site on cholinesterase enzyme
Donate a CARBAMYL group, which blocks the active site + prevents ACh from binding
Carbamyl groups are removed by slow hydrolysis (mins rather than miliseconds)
Increase duration of ACh activity in synapse
What is physostigmine used to treat?
Glaucoma- improves muscarinic response in eye, aiding intraocular fluid drainage
What is the half-life of physostigmine?
30 mins
What type of poisoning is physostigmine used to treat?
Atropine poisoning ( it increases the synaptic concentration of ACh so it can outcompete the atropine)
What type of compound are irreversible anticholinesterases?
Organophosphates
Describe the mechanism of action of irreversible anticholinesterases.
Rapidly react with enzyme active site, leaving a large blocking group
Bocking group is stable + resistant to hydrolysis so recovery requires production of new enzymes
What is ecothiopate used to treat?
Glaucoma
State some side-effects of ecothiopate.
Blurred vision Sweating Respiratory difficulty Hypotension GI disturbance and pain Bradycardia
What type of anticholinesterases can cross the blood-brain barrier? Give an example
Non-polar
e.g. physostigmine
Describe the effects of low and high doses of anticholinesterase drugs on CNS activity.
Low: Excitation with possibility of convulsions
High: unconsciousness, respiratory depression + death
Describe the treatment of organophosphate poisoning.
IV atropine: blocks the muscarinic receptors thus reducing the effect of the raised synaptic ACh concentration
Patient is put on a respiratory because of respiratory depression caused by excess ACh at the synapse (causing a depolarising block)
If found within the first few hours, the patient should be given IV PRALIDOXIME, which can unblock the enzymes
Where is the primary site of action of physostigmine?
Postganglionic parasympathetic synapse
What are other organophosphates commonly used as?
Insecticides
What is ecothiopate a potent inhibitor of?
Acetylcholinesterase
