Cholinomimetics Flashcards
What are cholinomimetics?
Drugs that mimic the action of acetylcholine in the body- parasympathomimetic drugs
How is acetylcholine synthesised?
From acetyl coA and choline by choline acetyltransferase (CAT)
What causes the exocytosis of Ach?
Depolarisation causes opening of voltage sensitive calcium channels and influx of calcium causes exocytosis of Ach
What is Ach broken down by?
Acetylcholinesterase
What is the most common muscarinic antagonist?
Atropine
What do muscarinic actions correspond to?
Parasympathetic stimulation
After atropine blockade of muscarinic actions, what do larger doses of acetylcholine induce?
Effects similar to those caused by nicotine
What are the three main muscarinic receptor subtypes?
M1- CNS excitation, salivary glands, stomach (release of HCl)
M2- Heart (decreases rate)
M3- Salivary glands, bronchial/visceral smooth muscle, sweat glands and eye
Where are M4 and M5?
In the CNS
What effect do muscarinic receptors normally have?
Excitatory
What is the exception to muscarinic receptors’ excitatory effect?
M2 receptors in the heart are inhibitory
What sort of receptors are muscarinic receptors?
Type 2 receptors (G protein coupled)
Which muscarinic receptors are Gq protein linked receptors?
M1, M3 and M5 (odds)
What sort of receptor are M2 and M4 (evens)?
Gi protein linked receptors
What do Gq protein receptors stimulate when bound to?
They stimulate PLC to increase production of IP3 and DAG
What do Gi protein receptors stimulate when bound to?
Inhibitory- reduces production of cAMP
What sort of receptor are nicotinic receptors?
Ligand gated ion channels
What are the 5 subunits the can make up the nicotinic receptor?
Alpha, beta, gamma, delta and epsilon
What do the subunits in the receptor determine?
Ligand binding properties of the receptor
What are the 2 main types of nicotinic receptor?
In the muscle= 2 alpha + beta + delta + epsilon
In the ganglion= 2 alpha + 3 beta
How does the effect of acetylcholine on nicotinic receptors compare to on muscarinic receptors?
Relatively weak
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)
Lacrimation
What does constriction of the sphincter pupillae do?
Constricts the pupil (mitosis) and increases drainage of intraocular fluid
What is glaucoma?
Increase in intraocular pressure
Why is glaucoma harmful?
It can damage the optic nerves and retina and it can ultimately lead to blindness
What generates aqueous humour?
Capillaries of the ciliary body
Where does aqueous humour go after being generated?
Anterior chamber of the eye
What is the role of the aqueous humour?
Supply oxygen and nutrients to the lens and cornea because they don’t have a blood supply
How does aqueous humour drain back into the venous system?
Through the canals of Schlemm
What is angle-closure glaucoma?
The angle between the cornea and the iris becomes narrowed- this reduces the drainage of the intraocular fluid via the canals of schlemm so intraocular pressure increases
What happens to patients with angle closure glaucoma when given a muscarinic agonist?
The iris contracts which opens up the angle and increases the drainage of intraocular fluid through the canals of Schlemm
How do muscarinic receptors have an inhibitory effect on the heart?
They decrease cAMP activity which leads to decreased Ca2+ entry which causes decreased cardiac output and increased K+ efflux which leads to decreased heart rate
Where are M2 receptors found in the heart?
In the atria and both nodes
What is parasympathetic control of blood vessels like?
Most blood vessels don’t have parasympathetic innervation but have receptors
How does acetylcholine act on vasculature?
It acts on vascular endothelial cells to stimulate NO release via M3 receptors which induces vascular smooth muscle relaxation which causes a decrease in TPR
What is the muscarinic effect on non-vascular smooth muscle that has parasympathetic innervation?
Opposite effect to vascular smooth muscle- it contracts
Lungs- constriction
Gut- increased peristalsis/motility
Bladder- increased bladder emptying
What is the muscarinic effects on exocrine glands?
Salivation
Increased bronchial secretions
Increased GI secretions
Increased sweating
What are the two types of cholinomimetic?
Directly acting (muscarinic receptor agonists) Indirectly acting
What are the two types of muscarinic receptor agonist?
Choline esters (bethanechol) Alkaloids (pilocarpine)
Why is pilocarpine a non-selective muscarinic agonist?
It has a some structural similarity to acetylcholine so it can stimulate all muscarinic receptors
What is the half life of pilocarpine?
3-4 hours
What is pilocarpine often used as a treatment for?
Glaucoma (constricts sphincter pupillae)
What are the side effects of pilocarpine use?
General effects of parasympathetic discharge: Blurred vision Sweating GI disturbance and pain Hypotension Respiratory distress
What sort of agonist is bethanechol due to its structure?
Its structure is only very slightly different to acetylcholine in terms of structure so it is an M3 receptor selective agonist
What effect does acetylcholinesterase have on bethanechol?
None because it is highly resistant to degradation by acetylcholinesterase
What is the half life on bethanechol?
3-4 hours
What is bethanechol mainly used for?
Assist bladder emptying and enhance gastric motility
What are the side effects of bethanecol?
Same as pilocarpine- parasympathetic discharge
What do indirectly acting cholinomimetic drugs do?
They inhibit acetylcholinesterase
How does inhibiting acetylcholinesterase lead to a cholinomimetic effect?
It increases the amount of acetylcholine in the synapse and by doing this, they increase the effect of normal parasympathetic stimulation
Give some examples of reversible anticholinesterases?
Physostigmine
Neostigmine
Donepezil
Give some examples of irreversible anticholinesterases?
Ecothiopate
Dyflos
Sarin
What are the two types of cholinesterase?
Acetylcholinesterase (true cholinesterase)
Butyrylcholinesterase (pseudocholinesterase)
Where is acetylcholinesterase found?
All cholinergic synapses
How fast to act is acetylcholinesterase?
Very rapid (>10000 reactions per second)
Where is butyrylcholinesterase found?
In plasma and most tissues but not in cholinergic synapses
How does the specificity of butyrylcholinesterase compare to acetylcholinesterase?
Acetylcholinesterase is highly specific for acetylcholine but butyrylcholinesterase has a broad substrate specificity- hydrolyses other esters e.g. suxamethonium
What does the broad specificity of butyrylcholinesterase mean that it is the principal reason for?
Low plasma acetylcholine
What is the effect of cholinesterase inhibitors in low doses?
Enhanced muscarinic activity
What is the effect of cholinesterase inhibitors in moderate doses?
Further enhanced muscarinic activity
Increased transmission at all autonomic ganglia- Ach conc will increase at all
What is the effect of cholinesterase inhibitors in high doses?
There is a depolarising block at the autonomic ganglia and neuromuscular junction- nicotinic receptors get overstimulated so shut down
How do reversible anti cholinesterase drugs like physostigmine and neostigmine work?
They compete with acetylcholine for the active site on acetylcholinesterase- they donate a carbamyl group to the enzyme blocking the active site
How are carbamyl groups removed from the active sites?
Slow hydrolysis which takes minutes and this increases duration of acetylcholine activity in synapse
Where does physostigmine primarily act?
Postganglionic parasympathetic synapse
What is the half life of physostigmine?
30 mins
What is physostigmine used to treat?
Glaucoma- increases drainage of intraocular fluid
Atropine poisoning
How is physostigmine treat atropine poisoning?
Atropine is a competitive muscarinic antagonist meaning that it is surmountable, physostigmine increases the concentration of Ach at the synapse so that it can outcompete atropine
What sort of compounds are irreversible anticholinesterase drugs?
Organophosphate compounds
How do irreversible anti cholinesterase drugs work?
They rapidly react with the enzyme active site, leaving a large blocking group which is stable and resistant to hydrolysis so recovery requires production of new enzymes which takes days/weeks
What is the only irreversible anti-cholinesterase drug in clinical use?
Ecothiopate
What is ecothiopate used to treat?
Glaucoma
How can anticholinesterase drugs reach the CNS to have an effect?
If they are non-polar they can cross the blood brain barrier
If low doses of anticholinesterase drugs reach the CNS, what effect do they have?
CNS excitation with possibility of convulsions
If high doses of anticholinesterase drugs reach the CNS, what effect do they have?
Unconsciousness, respiratory depression and death
What anticholinesterases are used to treat Alzheimer’s?
Donepezil and tacrine
What brain functions is acetylcholine important in?
Learning and memory
Why are organophosphates poisonous?
They cause an increase in muscarinic activity which leads to CNS excitation which leads to depolarising NM block
How do you treat organophosphate poisoning?
IV atropine
Respirator
If found in first few hours give pralidoxime (IV)
