Cholinomimetics Flashcards
What are cholinomimetics
Drugs that mimic the action of ACh
what is the reuptake mechanism of ACh
It doesn’t get reuptaken
Describe the synthesis, excretion, metabolism of ACh
Acetyl CoA and choline is converted to ACh and CoA. ACh is packaged into vesicles and secreted upon the arrival of an action potential. in the synapse it activates its receptor and then is broken down into choline and acetate by acetylcholinesterase
What enzyme breaks down ACh and what are the products
Acetylcholinesterase, choline and acetate
What is ACh synthesised from
Choline and acetyl CoA
What enzyme synthesises ACh, what’s the other product
choline acetyltransferase, CoA
What types of receptor ACh stimulate, nicotinic or muscarinic
Both
What drug is commonly used as a muscarinic antagonist
atropine
which branch of the NS corresponds with muscarinic stimulation
parasympathetic
what can happen if you administer a large dose of ACh after using atropine
you stimulate nicotinic receptors
Which muscarinic receptors are excitatory vs inhibitory
All 5 except M2 on the heart are excitatory
where are M2 receptors found
Heart
Where are M1 receptors found (3)
salivary glands, stomach and CNS
Where are M3 receptors found (4)
Salivary glands, bronchial/visceral smooth muscle, sweat glands, eye
What types of muscarinic receptors are found at: Salivary glands, bronchial/visceral smooth muscle, sweat glands, eye
M3
What types of muscarinic receptors are found at: the heart
M2
What types of muscarinic receptors are found at: salivary glands, stomach and CNS
M1
What are special about M2 receptors
Inhibitory
What are special about the hearts muscarinic receptors
Inhibitory
Where are M4 receptors found
CNS
Where are M5 receptors found
CNS
What type of receptor are muscarinic receptors
Type 2 G protein couples
What type of G protein receptors are M1, 3 and 5
Gq proteins linked to IP3 and DAG
What type of G protein receptors are M2 and 4
Gi proteins and linked to cAMP
Which muscarinic receptors are Gq proteins
M1, 3 and 5
Which muscarinic receptors are Gi proteins
M2 and 4
Which muscarinic receptors are IP3 and DAG linked
1, 3 and 5
Which muscarinic receptors are linked to cAMP
2 and 4
cAMP is which type of G protein?
Gi
IP3 and DAG is which type of G protein?
Gq
Gq protein uses which second messenger?
IP3 and DAG
Gi protein uses which second messenger?
cAMP
What type of receptors are nicotinic receptors?
Type 1 gated ion channels
Which types of muscarinic receptor is found in the CNS
1, 4 and 5
How many subunits on a nicotinic receptor and what are they called?
5 subunits, known as alpha beta gamma delta and epsilon
What determines the ligand binding properties of a nicotinic receptor
the subunit combination
Which branch of the NS uses nicotinic receptors
Both
What is the subunit combination of nicotinic receptors in muscle
2alpha, beta, delta, epsilon
What is the subunit combination of nicotinic receptors in ganglions
2alpha 3beta
2alpha 3beta is the nicotinic subunit combination for where
ganglions
2alpha, beta, delta, epsilon is the nicotinic subunit combination for where
Muscle
Where are ACh effects more potent, muscarinic or nicotinic receptors
Muscarinic
What type of muscarinic receptors are found in the eye
M3
What does contraction of the sphincter pupillae do
constricts the pupil and improves drainage of intraocular fluid by opening up pathway for aqueous humour, allowing the Canal of Schlemm to drain aqueous humour and reducing intraocular pressure
What does contraction of the ciliary muscle do
Accommodates for near vision by bulging the pupil
What’re the muscarinic effects of the eye (3)
Contraction of the sphincter pupillae, ciliary muscle and lacrimation
How does stimulation of the muscarinic receptor reduce intraocular pressure
Opening up the pathway for aqueous humour and allowing drainage via the canals of Schlemm
What effect does muscarinic stimulation have on the heart
reduction in cAMP and decreased cardiac output and heart rate
What effects does muscarinic stimulation have on smooth muscle
Stimulates NO release which induces vascular smooth muscle relaxation leading to a lower TPR
What effects does muscarinic stimulation have on the CVS system
Decreased heart rate (M2) (bradycardia).
Decreased cardiac output (due to decreased atrial contraction).
Vasodilation (stimulation of NO production).
All of this combined leads to a sharp drop in BP.
What effects does muscarinic stimulation have on non-vascular smooth muscle (3)
Lung: bronchoconstriction.
Gut: increased peristalsis (motility).
Bladder: increased bladder emptying
What effects does muscarinic stimulation have on the exocrine glands
Salivation.
Increased bronchial secretions.
Increased gastro-intestinal secretions (including gastric HCl production).
Increased sweating (SNS-mediated).
Summarise the effects of muscarinic stimulation (7)
Decreased heart rate. Decreased blood pressure. Increased sweating. Difficulty breathing. Bladder contraction. Gastrointestinal pain. Increased salivation and tears
Where are M2 receptors found in the heart
Atria and nodes
What type of muscarinic receptor is found on vascular endothelial cells
M3
Does the vasculature have a direct parasympathetic stimulation?
No
How does muscarinic stimulation result in a lower blood pressure
ACh acts on vascular endothelial cells to stimulate NO release via M3 AChR.
NO induces vascular smooth muscle relaxation, resulting in a decrease in TPR.
What is the difference in reaction to muscarinic stimulation by vascular and non-muscular smooth muscle
Smooth muscle that does have parasympathetic innervation responds in the opposite way to vascular muscle – it contracts
2 types of cholinomimetics
Choline esters and alkaloids
Example of a choline ester?
Bethanechol
Example of an alkaloid?
Pilocarpine
Give an example of a selective M3 agonist
Bethanechol
Metabolism of bethanechol?
Resistant to degradation as it is not broken down by AChesterase, half-life of 3/4 hours
What does bethanechol act on
M3
Side effects of bethanechol (5)
sweating, impaired vision, bradycardia, hypotension and respiratory difficulty
Give an example of a non-selective muscarinic agonist
Pilocarpine
what is betanechol used for
To assist bladder emptying and gastric motility
How much access to the brain does bethanechol have and why
Limited as it is not lipid soluble
How lipid soluble is bethanechol
Not very
How lipid soluble is pilocarpine
Good lipid solubility
Half life of pilocarpine?
3/4 hours
What is the use of pilocarpine? Why is this what it is ideal for
Local treatment for glaucoma, its lipid solubility allows it to readily pass through the cornea
side effects of pilocarpine? (6)
Blurred vision, sweating, gastro-intestinal disturbance and pain, hypotension, respiratory distress
Two types of cholinesterase enzymes?
Acetylcholinesterase and butyrylcholinesterase
Where is AChesterase found
All cholinergic synapses
What is the speed and selectivity of AChesterase
Very rapid and highly selective for ACh
Where is butyrylcholinesterase found
In plasma and most tissues but not cholinergic synapses
what is specificity of butyrylcholinesterase
Broad specificity so it hydrolyses other esters
What is the main reason for a low plasma ACh
Butyrylesterase
What are the 2 types of anticholinesterases
Reversible and irreversible
What is bethanechol an example of (2)
Choline ester, selective M3 agonist
What is pilocarpine an example of (2)
Alkaloid, non-selective muscarinic agonist
Example of a reversible anticholinesterase
Physostigmine
Example of an irreversible anticholinesterase
Ecothiopate
What does a low dose of an anticholinesterase do
Enhanced muscarinic activity
What does a moderate dose of anticholinesterase do (2)
Further enhanced msucarinic activity and increased transmission at all autonomic ganglia
What does high dose of anticholinesterase do
Toxic, depolarising block at all autonomic ganglia and NMJ
How does a reversible anticholinesterase work
Competes with ACh for active site of the cholinesterase. They donate a carbamyl group to the enzyme, blocking the active site and preventing ACh from binding. The carbamyl group is removed by slow hydrolysis (mins rather than msecs) and this increases the duration of ACh activity in the synapse
What is physostigmine an example of
Reversible anticholinesterase
What is ecothiopate an example of
Irreversible anticholinesterase
How does an irreversible anti cholinesterase work
organophosphate compounds. They rapidly phosphorylate the enzyme active site, leaving a large blocking group. This is stable and resistant to hydrolysis, meaning recovery may take weeks as it is mostly done with the production of new enzymes. An example is ecothiopate
What is physostigmine used for
acts at the postganglionic parasympathetic synapse and has a half life of around 30 mins. It is used in the treatment of glaucoma and helps to drain intraocular fluid. It can also be used to treat atropine poisoning.
What is ecothiopate used for
Used as eye drops in the treatment of glaucoma, acting to increase intraocular fluid drainage with a prolonged duration of action
What must be considered when using non-polar anticholinesterases
Effect on the CNS as they can cross the BBB.
Low doses can cause excitation with possibility of convulsions and high doses can result in unconsciousness, respiratory depression and even death
What drug class do organophosphates belong to
Irreversible anticholinesterases
how do you treat organophosphate poisoning
the use of atropine I.V., artificial respiration and pralidoxime I.V.. Pralidoxime can reverse an irreversible anticholinesterase if given within a few hours of phosphorylation, otherwise the phosphorylated enzyme ‘ages’ and becomes fully irreversibl
What drug is used to treat organophosphate poisoning
Pralidoxime
