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 – MOne “moan”= acid reflux so stomach (gastric acid secretion/ “heart burn” due to acid reflux) Other effects - salivary glands, CNS.
M2 – heart
M3 – mainly parasympathetic effects: salivary glands, bronchial smooth muscle constriction, visceral smooth muscle (constriction for GI motility), eyes (constriction pupil), VASODILATION (stimulates NO release) and sweat glands etc.
M4 and M5 are found in the CNS NOTE: muscarinic receptors are generally excitatory except for on the heart
What type of receptor are muscarinic,nicotinic and adrenergic receptors?
Muscarinic receptors (ACh) = G protein coupled
Nicotinic (ACh)= ionotropic
Adrenergic (NA)= G protein coupled
These are the 3 main receptors of the autonomic Nervous system
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 convertes PIP2 to IP3 and DAG
M2 and M4 = Gi protein linked receptors (inhibitory) – they decrease the production of cAMP
IP3 (inositol triphosphate) pathway leads to Ca2+ release. You can remember this because M3 leads to a lot of parasympathetic effects like bronchiole smooth muscle contraction etc
Describe the structure of nicotinic receptors. What determines its ligand binding properties?
Nicotinic receptors consist of 5 subunits (either 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), but also opens up trabecular meshwork for aqueous humour drainage (good for glaucoma)
- Constriction of sphincter pupillae (circular muscle of the eye) – this constricts the pupil and moves iris away from canal of schlemm, improving drainage of intraocular fluid (good for glaucoma)
- Lacrimation
note muscarinic receptors = parasympathetic NS
adrenergic receptors= sympathetic NS
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
see slide 11
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 in cardiac output (less contractility)
- It also triggers an increase in K+ efflux, which leads to a decrease in heart rate (resting membrane potential more negative)
NB heart parasympathetic innervation= vagus
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
Decreased stroke volume (decreased atrial contraction, if less blood moves from atria to ventricle the stroke volume will decrease as well)
= DECREASED CO
Decrease in total peripheral resistance (due to vasodilation)
=OVERALL DECREASED BP
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 (ie give the two types of directly acting cholinomimetics) and give an example of each.
Choline Esters – Bethanechol Alkaloids - Pilocarpine
Describe the selectivity of pilocarpine.
Non-selective muscarinic receptor agonist (muscarinic>nicotinic)
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
remember that muscarinic causes CONTRACTION on NON VASCULAR muscles, including bronchial smooth muscles, GI tract smooth muscles etc leading to bronchoconstrction and hence respiratory difficulty mentioned above. (see card 19)
Describe the selectivity of bethanechol.
M3 selective agonist
Clinical uses of bethanechol
Assist bladder emptying
Enhance gastric motility
State some side-effects of bethanechol.
Same as pilocarpine + bradycardia, nausea
sweating, impaired vision, bradycardia, hypotension, respiratory difficulty, nausea
What is the half-life of pilocarpine and bethanechol?
3-4 hours
What are the two types of anticholinesterase (ie indirectly acting cholinomimetic drugs)? Give examples of each.
Reversible – physostigmine, neostigmine, donepezil Irreversible – ecothiopate, dyflos, sarin
What are the two types of cholinesterase?
Acetylcholinesterase Butyrylcholinesterase
Compare the two cholinesterases
Location:
AChE: ALL cholinergic synapses
BChE: Plasma and most tissues NOT cholinergic synapses
Speed:
AChE has very RAPID action, probably quicker than BChE
Substrate specificity:
AChE: HIGHLY SELECTIVE for acetylcholine
BChE: Broad specificity- hydrolyses other substrates in addition to AChE eg suxamethonium
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) because it starts to affect the synapses which uses nicotinic AChreceptors
HIGH – depolarising block at autonomic ganglia and NMJ (the nicotinic receptors get overstimulated so they shut down). THIS IS BAD IF IT IS RESPIRATORY MUSCLE
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 (muscarinic cholinergic synapses)
What is physostigmine used to treat?
Glaucoma
atropine poisoning
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? What is special about its duration of action?
Glaucoma, acts to increase aqueuous humour drainage. Has a prolonged effect (since it is an irreversiible inhibitor)
State some side-effects of ecothiopate.
Blurred vision
Sweating
Respiratory difficulty
Hypotension
GI disturbance and pain
Bradycardia
ie symptoms of too much muscarinic stimulation
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
Describe the treatment of organophosphate poisoning.
Organophosphates are irreversible anticholinesterases.
IV atropine – this blocks the muscarinic receptors thus reducing the effect of the raised synaptic acetylcholine concentration Patient is put on artificial ventilation because of the respiratory depression caused by the excess acetylcholine at the NMJ of respiratory muscles (causing a depolarising block)
If found within the first few hours, the patient should be given IV PRALIDOXIME, which can unblock the AChE from organophosphates
