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
Nicotinic effects are those that an be replicated by nicotine
Comes from amanita muscaria and nicotiana tabacum
What can be given to abolish muscarinic effects?
Atropine (competitive muscarinic antagonist)
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, and sweat glands
M4 and M5 are found in the CNS
NOTE: muscarinic receptors are 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?
Nicotinic receptors consist of 5 subunits (alpha, beta, gamma, delta or epsilon)
The combination of subunits determines its ligand binding properties.
What are the two main types of nicotinic receptor? Describe their subunit composition.
Muscle and Ganglion
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?
The effects of acetylcholine are relatively weak on nicotinic compared to muscarinic
What three effects does muscarinic stimulation have on the eye?
Contraction of the ciliary muscle (accommodate for near vision)
Constriction of sphincter pupillae (circular muscle of the eye) – this constricts the pupil and increases drainage of intraocular fluid
Lacrimation
What is glaucoma?
Sustained raised intraocular pressure – this can cause damage to the optic nerves and retina and can lead to blindness
Where is aqueous humour produced? Describe its passage through the eye.
The capillaries in the ciliary body produce aqueous humour
Aqueous humour passes 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?
The angle between the cornea and the iris is narrowed which decreases the drainage of intraocular fluid through the canals of Schlemm
What are the effects of giving a muscarinic agonist to people with Angle-closure glaucoma?
This causes constriction of sphincter pupillae and opens up the angle to increase the drainage of intraocular fluid
Describe, in detail (including the mechanism), the muscarinic effects on the heart.
Binding of acetylcholine to the M2 receptors (Gi protein linked receptor) causes a decrease in cAMP production
This triggers a decrease in Ca2+ influx, which leads to a decrease incardiac output
It also triggers an increase in K+ efflux, which leads to a decrease in heart rate
Describe the muscarinic effects on the vasculature.
There is no direct parasympathetic innervation of blood vessels
However, there are muscarinic receptors on the endothelial cells
When stimulated, it triggers the production of nitric oxide (NO) from the endothelial cells, which causes vasodilation and a decrease in TPR
Summarise the muscarinic effects on the cardiovascular system.
Decrease in heart rate
Decrease in cardiac output (due to decreased atrial contraction)
Decrease in total peripheral resistance (due to vasodilation)
Decrease in blood pressure
Describe the muscarinic effects on non-vascular smooth muscle.
It is the opposite of muscarinic effects on vascular smooth muscle
It causes CONTRACTION of non-vascular smooth muscle
Lungs – bronchoconstriction
GI tract – increased motility
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 two types of cholinomimetic drug?
Directly Acting – muscarinic agonists
Indirectly Acting – acetylcholinesterase inhibitors -> increase the synaptic concentration of acetylcholine
State 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
It stimulates ALL muscarinic receptors
What is pilocarpine used to treat?
Glaucoma
State some 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, nausea
What is the half-life of pilocarpine and bethanechol?
3-4 hours
What are the two types of anticholinesterase? Give examples of each.
Reversible – physostigmine, neostigmine, donepezil
Irreversible – ecothiopate, dyflos, sarin
What are the two types of cholinesterase?
Acetylcholinesterase
Butyrylcholinesterase
Where is acetylcholinesterase found? Describe its properties.
It is found in ALL cholinergic synapses
It has very RAPID action and it is HIGHLY SELECTIVE for acetylcholine
Where is butyrylcholinesterase found? Describe its properties
Butyrylcholinesterase is found in plasma and most tissues but NOT in cholinergic synapses
It has a broad substrate specificity – it hydrolyses other esters e.g. suxamethonium
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 (nicotinic receptors)
HIGH – depolarising block at autonomic ganglia and NMJ (the nicotinic receptors get overstimulated so they shut down)
Describe the mechanism of action of reversible anticholinesterases.
Reversible anticholinesterases donate a CARBAMYL group, which blocks the active site of the acetylcholinesterase
Carbamyl groups are removed by slow hydrolysis (takes mins rather than miliseconds)
Which synapses does pilocarpine primarily act on?
Postganglionic parasympathetic synapses
What is physostigmine used to treat?
Glaucoma
What is the half-life of physostigmine?
30 mins
What type of poisoning is physostigmine used to treat?
Atropine poisoning (because it increases the synaptic concentration of acetylcholine so it can outcompete the atropine)
What type of compound are irreversible anticholinesterases?
Organophosphates
Describe the mechanism of action of irreversible anticholinesterases.
They rapidly react with the enzyme active site, leaving a large blocking group
The blocking group is stable and resistant to hydrolysis so recovery requires the 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?
Non-polar
Describe the effects of low and high doses of anticholinesterase drugs on CNS activity.
Low – CNS excitation with the possibility of convulsions
High – unconsciousness, respiratory depression and death
State two anticholinesterases that are used to treat Alzheimer’s disease
Donepezil
Tacrine
Describe the treatment of organophosphate poisoning.
IV atropine – this blocks the muscarinic receptors thus reducing the effect of the raised synaptic acetylcholine concentration
Patient is put on a respiratory because of the respiratory depression caused by the excess acetylcholine 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
