Cholinomimetics

Question 1

What are Cholinomimetics?

Answer 1

Cholinomimetics are drugs that mimic the action of acetylcholine in the body - they are parasympathomimetic drugs

Question 2

How is Acetylcholine synthesised?

Answer 2

From Acetyl-CoA + Choline

By Choline Acetyltransferase (CAT)

In Cholinergic neurones

Question 3

What is ACh broken down by?

Answer 3

Acetylcholinesterase

Question 4

Where are Muscarinic Receptors found?

Answer 4

Parasympathetic Effector organs

(Some SNS e.g. sweat glands)

Question 5

How can muscarinic effects be abolished?

Answer 5

With low doses of muscarinic antagonist Atropine

Question 6

What are the three main subsets of Muscarinic receptors?

Answer 6

M1

M2

M3

(M4 & M5 are in the CNS)

Question 7

What type of receptors are muscarinic receptors?

Answer 7

Type 2 - G-protein coupled

Question 8

Where are M1 receptors found?

Answer 8

• CNS - excitation
• Salivary Glands
• Stomach - stimulates release of HCl

Question 9

Where are M2 receptors found?

Answer 9

Heart - decreases HR

Question 10

Where are M3 receptors found?

Answer 10

• Salivary Glands
• Bronchial/Visceral Smooth Muscle
• Sweat Glands
• Eye

Question 11

Are Muscarinic receptors generally excitatory or inhibitory?

Answer 11

Generally excitatory except M2 receptors on heart which are inhibitory

Question 12

What type of G-proteins do the muscarinic receptors utilise?

Answer 12

• 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

Question 13

What type of receptors are Nicotinic receptors?

Answer 13

Type 1 - Ligand-gated Ion channels

Question 14

What are the two main types of Nicotinic receptors?

Answer 14

Those found in the muscle, and those found in ganglia

Question 15

What are nicotinic receptors made up from?

Answer 15

5 subunits: Alpha, Beta, Gamma, Delta, Epsilon

Subunit makeup determines the ligand binding properties of the receptor

Question 16

What subunits are Muscular nicotinic receptors comprised of?

Answer 16

2 alpha + beta + delta + epsilon

Question 17

What subunits are ganglionic nicotinic receptors comprised of?

Answer 17

2 alpha + 3 beta

Question 18

Are the effects of ACh stronger on muscarinic or nicotinic receptors?

Answer 18

Muscarinic

Question 19

What are the three main muscarinic effects on the eye?

Answer 19

• 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)

Question 20

What is Glaucoma?

Answer 20

Increase in intraocular pressure - this can cause damage to the optic nerves and retina and it can ultimately lead to blindness

Question 21

Describe the formation of Glaucoma:

Answer 21

1. Aqueous humour is generated by the capillaries of the ciliary body
2. The aqueous humour is generated and it flows into the anterior chamber of the eye
3. 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
4. In Angle-closure glaucoma, the angle between the cornea and the iris becomes narrowed
5. This narrowing reduces the drainage of intraocular fluid via the canals of Schlemm

Question 22

How can Glaucoma be treated?

Answer 22

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

Question 23

Describe the process of Muscarinic effects on the heart:

Answer 23

Question 24

What are the effects of M2 receptors on the heart?

Answer 24

Slows down heart rate and decreases cardiac output

Question 25

How can ACh effect the vasculature?

Answer 25

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

Question 26

What is the main Muscarinic effect on the Cardiovascular system

Answer 26

Decrease in Blood Pressure

Question 27

How does Muscarinic activity effect Vascular Smooth Muscle and Non-vascular smooth muscle?

Answer 27

Vascular Smooth Muscle: Dilation Non-vascular smooth muscle: Constriction

Question 28

What are the muscarinic effects on the Lungs, Gut and Bladder?

Answer 28

Lungs - bronchoconstriction Gut - increased peristalsis/motility Bladder - increased bladder emptying

Question 29

What are the Muscarinic effects on Exocrine glands?

Answer 29

* Salivation * Increased bronchial secretions * Increased GI secretions (including gastric HCl production) * Increased sweating (SNS-mediated)

Question 30

What are the seven main Muscarinic effects on the body:

Answer 30

1. Decreased heart rate 2. Decreased blood pressure 3. Increased sweating 4. Difficulty breathing 5. Bladder emptying 6. GI pain 7. Increased salivation and tears

Question 31

What are the two types of Cholinomimetic?

Answer 31

Directly-acting: Muscarinic Receptor Agonists Indirectly-acting: Acetylcholinesterase inhibitors

Question 32

What are the two types of Muscarinic receptor agonists and give an example for each:

Answer 32

Choline esters (bethanechol) Alkaloids (pilocarpine)

Question 33

Is Pilocarpine selective or non-selective and why?

Answer 33

Non-selective - it can stimulate all Muscarinic receptor types It has only some structural similarity to ACh

Question 34

What is Pilocarpine used to treat?

Answer 34

**Glaucoma** It constricts sphincter pupillae and opens up the canals of Schlemm to increase the drainage of intraocular fluid

Question 35

Is Bethanechol a selective or non-selective Muscarinic Agonist, and why?

Answer 35

Selective M3 agonist It only differs from ACh by one methyl group

Question 36

What is Bethanechol used for?

Answer 36

It is mainly used to assist bladder emptying and enhance gastric motility

Question 37

What are the side effects of Pilocarpine and Bethanechol?

Answer 37

The general effects of parasympathetic discharge: * Sweating * Impaired vision * Nausea * Bradycardia * Hypotension * Respiratory difficulty

Question 38

How do indirect Cholinomimetics work?

Answer 38

They inhibit Acetylcholinesterase They increase the build up of ACh in the synapse They increase the effect of normal parasympathetic stimulation

Question 39

Name a reversible and a non-reversible Anticholinesterase:

Answer 39

Reversible: Physostigmine Non-reversible: Ecothiopate

Question 40

What is Acetylcholinesterase? Where is it found?

Answer 40

Converts ACh to Choline and Acetate - Very rapid and highly selective All cholinergic synapses

Question 41

What is Butyrylcholinesterase? Where is it found?

Answer 41

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

Question 42

What happens with Low and Moderate doses of Anticholinesterases?

Answer 42

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

Question 43

What happens when a high dose of an anticholinesterase is administered?

Answer 43

Depolarising block at autonomic ganglia and neuromuscular junction. The nicotinic receptors get overstimulated so they shut down

Question 44

What types of drug are Physostigmine and Neostigmine, and how do they work?

Answer 44

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

Question 45

How are Physostigmine and Neostigmine reversed by the body?

Answer 45

Carbamyl groups are removed by slow hydrolysis (this takes minutes rather than miliseconds)

Question 46

What is Physostigmine used to treat?

Answer 46

Glaucoma Atropine poisoning (Physostigmine increases the concentration of acetylcholine at the synapse so that the acetylcholine can outcompete the atropine)