Cholinomimetics

Question 1

What are cholinomimetic drugs?

Answer 1

Drugs that mimic other molecules and affect the parasympathetic nervous system.

i.e. they are ACh mimicking drugs

Question 2

How is acetylcholine (ACh) released into the synapse?

Answer 2

1. Acetyl CoA and choline are converted into ACh and CoA using enzyme choline acetyltransferase.
2. ACh is packaged out into vesicles and exocytoses into the cleft
3. ACh binds to receptor on the post-synaptic neurone to have its effect
4. ACh is broken down by acetylcholinesterase into choline and acetate.

Question 3

Briefly describe the effects of atropine

Answer 3

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

Question 4

Where do nicotinic receptors exist?

Answer 4

Remember nicotinic receptors exist on all pre-ganglionic neuronal cell bodies (and ACh acts on all of them throughout the ANS)

Question 5

What is the agonist for nicotinic receptors?

Answer 5

Acetylcholine (ACh)

Question 6

Where are muscarinic receptors present?

Answer 6

They are present on effector organs for the PNS and effector organs like the sweat glands for the SNS.

Question 7

What are the 3 main subtypes of muscarinic receptors?

Answer 7

• 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

Question 8

What type of receptor are the muscarinic receptors?

Answer 8

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.

Question 9

What is the difference between the G proteins of the M1 &M3 receptor and the M2 receptors?

Answer 9

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.

Question 10

what type of receptor are nicotinic receptors?

Answer 10

Nicotinic receptors are ligand gated ion channels. They are made up of 5 subunits: α β γ δ ε

Question 11

What is the significance behind the subunits for the nicotinic receptors?

Answer 11

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.

Question 12

What are the 2 main types of nicotinic receptors you can get?

Answer 12

1. Muscle type (2 α, β,δ, ε)
2. Ganglion type (2α and 3β)

effects of ACh are relatively weak

Question 13

What are the target systems for the muscarinic cholinergic target systems- muscarinic receptors that use ACh

Answer 13

• eye
• salivary glands
• sweat glands
• lung
• heart
• gut
• bladder
• vasculature

Question 14

What happens to the eye if the muscarinic receptors are stimulated?

(hint ^when PNS> SNS)

Answer 14

1. Contraction of the ciliary muscle (accommodation for near vision). The lens bulges and becomes more convex. For looking for close objects need bulging lens.
2. Sphincter pupillae contraction- circular muscle in the iris. This causes constriction of the pupil (miosis) and improves drainage of intraocular fluid
3. Lacrimation- tears

Question 15

where is aqueous humour produced in the eye?

Answer 15

In the ciliary body

Question 16

What is the role of aqueous humour?- describe its movement

Answer 16

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.

Question 17

Describes what happens to the eye in glaucoma

Answer 17

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.

Question 18

Where are M2 receptors present?

Answer 18

In the heart. More specifically-the atria, the SAN and the AVN.

Question 19

What happens if ACh binds to M2 receptors?

Answer 19

There is an inhibitory effect.

Negative ionotropic- there is a reduction in HR and CO

Question 20

How does ACh binding to M2 receptors bring about negative ionotropic effects?

Answer 20

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

Question 21

Do blood vessels have parasympathetic innervation?

Answer 21

NO- most blood vessels do not have PSNS innervation

Question 22

How does ACh stimulation of muscarinic receptors affect blood vessels?

Answer 22

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.

Question 23

What are the muscarinic effects on the cardiovascular system?

Answer 23

• 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

Question 24

What are the muscarinic effects of exocrine glands?

Answer 24

• Salivation
• Increased bronchial secretions
• Increased gastro-intestinal secretions (including gastric HCl production)
• Increased sweating (SNS mediated)

Question 25

Summarise all muscarinic effects

Answer 25

• Decreased HR
• Decreased BP
• Increased sweating
• Difficulty breathing
• Bladder contraction
• GI pain
• Increased salivation and tears

Question 26

So recap- what are cholinomimetic drugs?

Answer 26

Drugs that imitate ACh actions- they will act as agonists at muscarinic receptors

Question 27

Give 2 examples of cholinomimetic drugs

Answer 27

• Alkaloids
• Choline esters

e.g. bethanechol and pilocarpine

Question 28

What makes pilocarpine and bethanechol able to imitate ACh?

Answer 28

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.

Question 29

Describe pilocarpine actions

Answer 29

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.

Question 30

Describe bethanechol actions

Answer 30

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

Question 31

What is the difference between directly and indirectly acting cholinomimetic drugs?

Answer 31

Directly acting- the drug binds to the receptor instead of the receptors

Indirectly acting- Targets the enzyme that breaks down Ach (acetylcholinesterases).

Question 32

what do indirectly acting cholinomimetic drugs do?

Answer 32

Targets the enzyme that breaks down Ach (acetylcholinesterases). It increases the effect on normal parasympathetic nerve stimulation.

Question 33

you can get reversible and irreversible effects on the anticholinesterases- name one reversible and irreversible drug

Answer 33

Reversible-physostigmine

Irreversible-ectothiopate

Question 34

what are anticholinesterases like as enzymes?

Answer 34

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.

Question 35

What is butyrylcholinesterase?

Answer 35

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

Question 36

What is suxamethonium

Answer 36

it is a neuromuscular blocking drug- also a muscarinic agonist.

Question 37

Why is butyrylcholinesterase so important?

Answer 37

It is the reason for low ACh plasma levels

Question 38

What is physostigmine?

Answer 38

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.

Question 39

Describe the action of ecothiopate

Answer 39

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.

Question 40

How do you treat organophosphate poisoning?

Answer 40

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

Question 41

The effects of cholinesterase inhibitors depends on their dose…

Answer 41