6: Cholinomimetics

Question 1

Define cholinomimetics

Answer 1

drugs that mimic action of ACh in the body – parasympathomimetic drugs

Question 2

Eg of muscarinic antagonist

Answer 2

atropine - competitive muscarinic antagonist

Question 3

Muscarinic effects in eye

Answer 3

• Ciliary muscle contraction: accommodates for near vision
• Sphincter pupillae contraction (circular muscle of the iris): this constricts the pupil (miosis) + increases drainage of intraocular fluid
• Lacrimation (tears)

Question 4

How does glaucoma occur

Answer 4

Glaucoma is an increase in intraocular pressure - this can cause damage to the optic nerves and retina and can ultimately lead to blindness.

1. Fenestrated capillaries of the ciliary body generates aqueous humour
2. It flows into the anterior chamber of the eye. Role: supply O2 + nutrients to the lens + cornea bc they don’t have a blood supply.
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.

Question 5

What is angle closure glaucoma

Answer 5

The angle btwn the cornea + iris narrows, reducing drainage of intraocular fluid via canals of schlemm

Question 6

How is angle closure glaucoma treated

Answer 6

Muscarinic agonist - causes iris contraction, opening of angle, incresing drainage of intraocular fluid through canals of Schlemm.

Question 7

Muscarinic effects in heart

Answer 7

M2 receptors are INHIBITORY. It slows down the heart rate. M2 receptors are found in the atria and in both nodes. It causes a negative inotropic (contractility) and chronotropic (HR) effect. It reduces cAMP in cardiomyocytes + pacemaker cells, decreasing Ca2+ entry (decreasing CO), increasing K+ effluc (decreasing HR).

Question 8

Muscarinic effects on vasculature

Answer 8

Receptors sit on vascular endothelial cells.

1. ACh acts on vascular endothelial cells to stimulate NO release via M3 receptors.
2. NO induces vascular smooth muscle relaxation - vasodilation
3. This results in a decrease in TPR

Question 9

Muscarinic effects on CVS

Answer 9

• ↓HR
• ↓CO (due to decreased atrial contraction)
• Vasodilation (via stimulation of NO release)

=Drop in BP

Question 10

Muscarinic effects on non-vascular SM (lungs, gut, bladder)

Answer 10

Non-vascular SM that has PS innervation responds in the opposite way to vascular SM - it contracts
• Lungs - bronchoconstriction
• Gut - increased peristalsis/motility
• Bladder - increased bladder emptying

Question 11

Muscarinic effects on exocrine glands

Answer 11

• Salivation
• ↑bronchial secretions
• ↑GI secretions (including gastric HCl production)
• ↑sweating (SNS-mediated)

Question 12

2 types of cholinomimetic

Answer 12

Directly Acting

Indirectly acting

Question 13

Directly acting cholinomimetic drugs are which type of agonist and give the 2 types

Answer 13

Muscarinic receptor agonists
2 types:
- choline esters
- alkaloids

Question 14

Example of choline ester

Answer 14

bethanechol - only diff btwn that and ACh is one methyl group. So is v good muscarinic agonist

Question 15

Example of alkaloid

Answer 15

Pilocarpine - non-selective muscarinic agonist as some structure similarity btwn it and ACh

Question 16

Example of M3 receptor selective agonist

Answer 16

Bethanechol - v slighlty diff to ACh

Question 17

Which directly acting cholinomimetic drug is used in treatment of glaucoma

Answer 17

pilocarpine

Question 18

Which directly acting cholinomimetic drug is resistant to acetylcholinesterase

Answer 18

bethanechol

Question 19

Uses of bethanechol

Answer 19

assist bladder emptying and enhance gastric motility

Question 20

side effects of pilocarpine

Answer 20

• Blurred vision
• Sweating
• GI disturbance and pain
• Hypotension
• Respiratory distress

Question 21

Side effects of bethanechol

Answer 21

• Sweating
• Impaired vision
• Nausea
• Bradycardia
• Hypotension
• Respiratory difficulty

Question 22

How do indirectly acting cholinomimetic drugs work

Answer 22

Inhibit acetylcholinesterase, increasing amount of ACh building up in the synapse, thus increasing effect of normal PS nerve stimulation.

Question 23

2 types of indirectly acting cholinomimetic drugs

Answer 23

• Reversible Anticholinesterases:

* Irreversible Anticholinesterases:

Question 24

Examples of reversible anticholinesterases

Answer 24

PHYSOSTIGMINE, Neostigmine, Donepezil

Question 25

Examples of irreversible anticholinesterases

Answer 25

ECOTHIOPATE, Dyflos, Sarin

Question 26

2 types of cholinesterases

Answer 26

• Acetylcholinesterase (true or specific cholinesterase)

* Butyrylcholinesterase (pseudocholinesterase)

Question 27

How does Acetylcholinesterase work

Answer 27

It is highly selective for acetylcholine
Serine AA residue on active site of AChE – ACh binds to this active site. Hydroxyl group of serine splits off the acetyl group into choline + acetate, inactivating it rapidly.

Found in all choliinergic synapses

Question 28

Where is Butyrylcholinesterase found

Answer 28

plasma and in most tissues but not in cholinergic synapses. Has broad substrate specificty

Question 29

How do reversibe anticholinesterases work

Answer 29

They compete with ACh for the active site on acetylcholinesterase. They donate a carbamyl group to the enzyme, blocking the active site and preventing ACh from binding.
• Carbamyl groups are removed by slow hydrolysis (this takes minutes rather than miliseconds)
• This increases the duration of acetylcholine activity in the synapse

Question 30

Physostigmine (where it acts, half life, uses)

Answer 30

Where: postgang PS synapse
Half life: 30mins

Use: Glaucoma - increases drainage of intraocular fluid
Use: Atropine poisoning - a competitive muscarinic antagonist means that it’s surmountable. Physostigmine increases [ACh] at synapse so ACh can outcompete atropine.

Is non-polarso can cross BBB

Question 31

How do irreversible anticholinesterase drugs work

Answer 31

Irreversible anticholinesterase drugs are organophosphate compounds. They rapidly react with the enzyme active site, leaving a large blocking group. The blocking group is stable and resistant to hydrolysis so recovery requires the production of new enzymes (this takes days/weeks)

Question 32

Ecothiopate (how it acts, uses)

Answer 32

Potent inhibitor of acetylchoninesterase
Slow reactivation of the enzyme by hydrolysis takes several days

Uses: glaucoma treatment, increases drainage of intraocular fluid and has prolonged duration of action

Question 33

Effects of Cholinesterase Inhibitors at low, moderate and high doses

Answer 33

• Low dose: enhanced muscarinic activity. CNS excitation w possibility of convulsions
• Moderate dose: Further enhancement of muscarinic activity, increased transmission at all autonomic ganglia (nAChRs). This is bc the anticholinesterase increases the [ACh] at all cholinergic synapses, muscarinic and nicotinic
• High dose: depolarising block at autonomic ganglia (block on nAChrs) and NMJ. The nicotinic receptors get overstimulated so they shut down. May see unconsciousness, respiratory depression + death

Question 34

Organophosphate poisoning

Answer 34

Accidental exposure to organophosphates used in insecticides, or deliberate use in nerve agents can cause severe toxicity (increase in muscarinic activity = CNS excitation = depolarising NM block)

Question 35

Treatment of organophosphate poisoning

Answer 35

IV atropine: because organophosphate poisoning results in a massive reduction in the activity of acetylcholinesterase which leads to a massive increase in synaptic [ACh]. To block the ACh from over-stimulating the receptors you give a muscarinic antagonist (atropine)

PT put on respirator bc of respiratory depression

If found in the first few hours the patient can be given Pralidoxime (IV) - this unblocks the enzymes