Cholinomimetics Flashcards
What are cholinomimetic drugs?
Drugs that mimic other molecules and affect the parasympathetic nervous system.
i.e. they are ACh mimicking drugs
How is acetylcholine (ACh) released into the synapse?
- Acetyl CoA and choline are converted into ACh and CoA using enzyme choline acetyltransferase.
- ACh is packaged out into vesicles and exocytoses into the cleft
- ACh binds to receptor on the post-synaptic neurone to have its effect
- ACh is broken down by acetylcholinesterase into choline and acetate.
Briefly describe the effects of atropine
Atropine is a muscarinic antagonist.
Muscarinic actions can correspond to those of parasympathetic stimulation. After atropine blockade of muscarinic receptors, larger doses of ACh can induce effects similar to those caused by nicotine
Where do nicotinic receptors exist?
Remember nicotinic receptors exist on all pre-ganglionic neuronal cell bodies (and ACh acts on all of them throughout the ANS)
What is the agonist for nicotinic receptors?
Acetylcholine (ACh)
Where are muscarinic receptors present?
They are present on effector organs for the PNS and effector organs like the sweat glands for the SNS.
What are the 3 main subtypes of muscarinic receptors?
- M1- CNS, stomach (parietal cells), salivary glands
- M2- Heart
- M3- Salivary lands, bronchial/ visceral smooth muscle, sweat glands, eye
There are also M4 and M5 receptors but they are not relevant right now
What type of receptor are the muscarinic receptors?
All M receptors are G protein-coupled receptors. They have 7 transmembrane segments. Agonist binds on the outside. There is a loop in the membrane which is connected to the G protein, beta and gamma subunits.
What is the difference between the G proteins of the M1 &M3 receptor and the M2 receptors?
M1 and M3 are bound to the stimulatory Gq protein- increase in IP3 and DAG
The M2 receptor is inhibitory- it binds to a Gi protein- this reduces the cAMP in the cell.
what type of receptor are nicotinic receptors?
Nicotinic receptors are ligand gated ion channels. They are made up of 5 subunits: α β γ δ ε
What is the significance behind the subunits for the nicotinic receptors?
You can have any combo of the 5 subunits ( but you need the 5).The subunit combo determines the ligand binding properties of the receptor.
What are the 2 main types of nicotinic receptors you can get?
- Muscle type (2 α, β,δ, ε)
- Ganglion type (2α and 3β)
effects of ACh are relatively weak
What are the target systems for the muscarinic cholinergic target systems- muscarinic receptors that use ACh
- eye
- salivary glands
- sweat glands
- lung
- heart
- gut
- bladder
- vasculature
What happens to the eye if the muscarinic receptors are stimulated?
(hint ^when PNS> SNS)
- Contraction of the ciliary muscle (accommodation for near vision). The lens bulges and becomes more convex. For looking for close objects need bulging lens.
- Sphincter pupillae contraction- circular muscle in the iris. This causes constriction of the pupil (miosis) and improves drainage of intraocular fluid
- Lacrimation- tears
where is aqueous humour produced in the eye?
In the ciliary body
What is the role of aqueous humour?- describe its movement
Flows forwards into the front chambers of the eye (anterior). It bathes the lens and the cornea (because the lens doesn’t have a blood supply). Canal of shlemm is where the humour drains back into the venous system.
Describes what happens to the eye in glaucoma
In glaucoma, the iris becomes ruffled and this reduces drainage angle, the rate of drainage is reduced. The intraocular pressure increases. This can damage the retina and the optic nerve, causing blindness.
Where are M2 receptors present?
In the heart. More specifically-the atria, the SAN and the AVN.
What happens if ACh binds to M2 receptors?
There is an inhibitory effect.
Negative ionotropic- there is a reduction in HR and CO
How does ACh binding to M2 receptors bring about negative ionotropic effects?
ACh decreases cAMP, therefore decreasing CA 2+ entry into the cell and decreasing cardiac output. Also decreased cAMP means that there is increased K+ efflux and decreased heart rate
Do blood vessels have parasympathetic innervation?
NO- most blood vessels do not have PSNS innervation
How does ACh stimulation of muscarinic receptors affect blood vessels?
ACh acts on endothelial cells and stimulate NO release.
ACh bind to M3 AChRs.
They are on the endothelial cells, not the smooth muscle cells. NO is a vasodilator and causes relaxation of smooth muscles and therefore dilation of blood vessels.
The effect on blood vessels is a secondary effect.
What are the muscarinic effects on the cardiovascular system?
- Decreased HR (bradycardia)
- Decreased Cardiac output (due to decreased atrial contraction)
- Vasodilation (stimulation of NO production)
All of these combined can lead to a sharp drop in BP
What are the muscarinic effects of exocrine glands?
- Salivation
- Increased bronchial secretions
- Increased gastro-intestinal secretions (including gastric HCl production)
- Increased sweating (SNS mediated)
Summarise all muscarinic effects
- Decreased HR
- Decreased BP
- Increased sweating
- Difficulty breathing
- Bladder contraction
- GI pain
- Increased salivation and tears
So recap- what are cholinomimetic drugs?
Drugs that imitate ACh actions- they will act as agonists at muscarinic receptors
Give 2 examples of cholinomimetic drugs
- Alkaloids
- Choline esters
e.g. bethanechol and pilocarpine
What makes pilocarpine and bethanechol able to imitate ACh?
There are structural similarities between Ach and pilocarpine and bethanechol. There are similar functional groups (e.g. there’s an addition of methyl group). Therefore, they are able to activate the muscarinic receptors.
Describe pilocarpine actions
Pilocarpine is a non-selective muscarinic agonist (M1, M2 and M3).
Good lipid solubility.
Used to flatten out the iris (to help glaucoma).
Unwanted effects: blurred vision, sweating, GI problems and pain.
Describe bethanechol actions
M3 AChR selective agonist.
Resistant to degradation- not metabolised by acetylcholinesterases. Water-soluble- limited access to the brain. Stimulates bladder emptying and enhances gastric mobility.
Side effects: sweating, blurred vision, bradycardia, hypotension and respiratory difficulty.
Administered orally
What is the difference between directly and indirectly acting cholinomimetic drugs?
Directly acting- the drug binds to the receptor instead of the receptors
Indirectly acting- Targets the enzyme that breaks down Ach (acetylcholinesterases).
what do indirectly acting cholinomimetic drugs do?
Targets the enzyme that breaks down Ach (acetylcholinesterases). It increases the effect on normal parasympathetic nerve stimulation.
you can get reversible and irreversible effects on the anticholinesterases- name one reversible and irreversible drug
Reversible-physostigmine
Irreversible-ectothiopate
what are anticholinesterases like as enzymes?
They are found in all cholinergic synapses (peripheral and central)
Very rapid action (hydrolysis is more than 10,000 reactions per second)
as an enzyme, it is highly selective for ACh.
Ach binds to the active site of the enzyme (serine group). The hydroxyl group splits the Ach into acetate and choline.
What is butyrylcholinesterase?
it is a pseudocholinesterase found in other places and not cholinergic synaptic clefts.
It is found in the plasma- broad specificity and hydrolyses other esters too like suxamethonium
What is suxamethonium
it is a neuromuscular blocking drug- also a muscarinic agonist.
Why is butyrylcholinesterase so important?
It is the reason for low ACh plasma levels
What is physostigmine?
it is a reversible anticholinesterase.
It competes with ACh for the binding site on the anticholinesterase enzyme.
ACh cannot bind to it because they leave a carbanyl group on the enzyme. The carbamyl group takes a while (minutes) to be released for the enzyme to work again.
Therefore, there is an increase in Ach.
Describe the action of ecothiopate
It is an irreversible anticholinesterase drug ( as well as organophosphate)
They leave a massive blocking group on the cholinesterase enzyme. The block is stable and resistant to hydrolysis. Recovery can take days and weeks.
How do you treat organophosphate poisoning?
Organophosphates are used in insecticides, or deliberately used as nerve agents and can cause severe toxicity (there is an increased muscarinic activity and CNS excitation, depolarising NM block).
The treatment is atropine (IV), artifical respiration and pralidoxime
The effects of cholinesterase inhibitors depends on their dose…
