Cholinomimetics Flashcards
What are Cholinomimetics?
Cholinomimetics are drugs that mimic the action of acetylcholine in the body - they are parasympathomimetic drugs
How is Acetylcholine synthesised?
From Acetyl-CoA + Choline
By Choline Acetyltransferase (CAT)
In Cholinergic neurones
What is ACh broken down by?
Acetylcholinesterase
Where are Muscarinic Receptors found?
Parasympathetic Effector organs
(Some SNS e.g. sweat glands)
How can muscarinic effects be abolished?
With low doses of muscarinic antagonist Atropine
What are the three main subsets of Muscarinic receptors?
M1
M2
M3
(M4 & M5 are in the CNS)
What type of receptors are muscarinic receptors?
Type 2 - G-protein coupled
Where are M1 receptors found?
- CNS - excitation
- Salivary Glands
- Stomach - stimulates release of HCl
Where are M2 receptors found?
Heart - decreases HR
Where are M3 receptors found?
- Salivary Glands
- Bronchial/Visceral Smooth Muscle
- Sweat Glands
- Eye
Are Muscarinic receptors generally excitatory or inhibitory?
Generally excitatory except M2 receptors on heart which are inhibitory
What type of G-proteins do the muscarinic receptors utilise?
- M1, M3, M5 = Gq protein-linked receptor → stimulates PLC to increase the production of IP3 and DAG
- M2, M4 = Gi protein-linked receptor → inhibitory - reduces the production of cAMP
Odds = Gq
Evens = Gi
What type of receptors are Nicotinic receptors?
Type 1 - Ligand-gated Ion channels
What are the two main types of Nicotinic receptors?
Those found in the muscle, and those found in ganglia
What are nicotinic receptors made up from?
5 subunits: Alpha, Beta, Gamma, Delta, Epsilon
Subunit makeup determines the ligand binding properties of the receptor
What subunits are Muscular nicotinic receptors comprised of?
2 alpha + beta + delta + epsilon
What subunits are ganglionic nicotinic receptors comprised of?
2 alpha + 3 beta
Are the effects of ACh stronger on muscarinic or nicotinic receptors?
Muscarinic
What are the three main muscarinic effects on the eye?
- Contraction of the ciliary muscle - accommodates for near vision
- Contraction of sphincter pupillae (circular muscle of the iris) - this constricts the pupil (miosis) and increases drainage of intraocular fluid
- Lacrimation (tears)
What is Glaucoma?
Increase in intraocular pressure - this can cause damage to the optic nerves and retina and it can ultimately lead to blindness
Describe the formation of Glaucoma:
- Aqueous humour is generated by the capillaries of the ciliary body
- The aqueous humour is generated and it flows into the anterior chamber of the eye
- The aqueous humour diffuses forwards across the lens, then across the cornea and it drains through the canals of Schlemm back into the venous system
- In Angle-closure glaucoma, the angle between the cornea and the iris becomes narrowed
- This narrowing reduces the drainage of intraocular fluid via the canals of Schlemm
How can Glaucoma be treated?
If you give patients a muscarinic agonist and cause contraction of the iris, this opens up the angle and increases the drainage of intraocular fluid through the canals of Schlemm
Describe the process of Muscarinic effects on the heart:
What are the effects of M2 receptors on the heart?
Slows down heart rate and decreases cardiac output
How can ACh effect the vasculature?
Most blood vessels do not have parasympathetic innovation but do have muscarinic receptors
- ACh in the blood acts on vascular endothelial cells to stimulate NO release via M3 receptors
- NO induces vascular smooth muscle relaxation
- This results in a decrease in TPR
What is the main Muscarinic effect on the Cardiovascular system
Decrease in Blood Pressure
How does Muscarinic activity effect Vascular Smooth Muscle and Non-vascular smooth muscle?
Vascular Smooth Muscle: Dilation
Non-vascular smooth muscle: Constriction
What are the muscarinic effects on the Lungs, Gut and Bladder?
Lungs - bronchoconstriction
Gut - increased peristalsis/motility
Bladder - increased bladder emptying
What are the Muscarinic effects on Exocrine glands?
- Salivation
- Increased bronchial secretions
- Increased GI secretions (including gastric HCl production)
- Increased sweating (SNS-mediated)
What are the seven main Muscarinic effects on the body:
- Decreased heart rate
- Decreased blood pressure
- Increased sweating
- Difficulty breathing
- Bladder emptying
- GI pain
- Increased salivation and tears
What are the two types of Cholinomimetic?
Directly-acting: Muscarinic Receptor Agonists
Indirectly-acting: Acetylcholinesterase inhibitors
What are the two types of Muscarinic receptor agonists and give an example for each:
Choline esters (bethanechol)
Alkaloids (pilocarpine)
Is Pilocarpine selective or non-selective and why?
Non-selective - it can stimulate all Muscarinic receptor types
It has only some structural similarity to ACh
What is Pilocarpine used to treat?
Glaucoma
It constricts sphincter pupillae and opens up the canals of Schlemm to increase the drainage of intraocular fluid
Is Bethanechol a selective or non-selective Muscarinic Agonist, and why?
Selective M3 agonist
It only differs from ACh by one methyl group
What is Bethanechol used for?
It is mainly used to assist bladder emptying and enhance gastric motility
What are the side effects of Pilocarpine and Bethanechol?
The general effects of parasympathetic discharge:
- Sweating
- Impaired vision
- Nausea
- Bradycardia
- Hypotension
- Respiratory difficulty
How do indirect Cholinomimetics work?
They inhibit Acetylcholinesterase
They increase the build up of ACh in the synapse
They increase the effect of normal parasympathetic stimulation
Name a reversible and a non-reversible Anticholinesterase:
Reversible: Physostigmine
Non-reversible: Ecothiopate
What is Acetylcholinesterase?
Where is it found?
Converts ACh to Choline and Acetate
- Very rapid and highly selective
All cholinergic synapses
What is Butyrylcholinesterase?
Where is it found?
Hydrolyses many esters inc. ACh
Found in Plasma and most tissues but not Cholinergic synapses
Responsible for low level of Plasma ACh
Shows genetic variation
What happens with Low and Moderate doses of Anticholinesterases?
LOW dose:
Enhanced muscarinic activity
MODERATE dose:
- Further enhancement of muscarinic activity
- Increased transmission at ALL autonomic ganglia (nAChRs)
- This is because the anticholinesterase increases the acetylcholine
- concentration at ALL cholinergic synapses, muscarinic and nicotinic
What happens when a high dose of an anticholinesterase is administered?
Depolarising block at autonomic ganglia and neuromuscular junction.
The nicotinic receptors get overstimulated so they shut down
What types of drug are Physostigmine and Neostigmine, and how do they work?
Reversible anticholinesterases
They compete with acetylcholine for the active site on acetylcholinesterase
These drugs donate a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding
Increases the duration of ACh activity in the synapse
How are Physostigmine and Neostigmine reversed by the body?
Carbamyl groups are removed by slow hydrolysis
(this takes minutes rather than miliseconds)
What is Physostigmine used to treat?
Glaucoma
Atropine poisoning
(Physostigmine increases the concentration of acetylcholine at the synapse so that the acetylcholine can outcompete the atropine)
