Cholinomimetics

Question 1

Describe the synthesis, release and metabolism of acetylcholine

Answer 1

ACh+choline ->ACh and CoA (choline acetyltransferase) ->vesicles
AP opens voltage sensitive of calcium channels-> influx of calcium-> release of ACh into synaptic cleft->ACh binds to post-synamptic receptors to generate response-> acetylchominesterase (bound to basement membrane in synaptic cleft) breaks down ACh -> taken back into pre-synaptic neurone

Question 2

What is an example of a competitive muscarinic cholinoreceptor agaonist?

Answer 2

atropine

Question 3

What are the subtypes of muscarinic receptors? Where are they found?

Answer 3

M1 - Salivary glands, stomach, CNS
M2 - Heart
M3 - Salivary and sweat glands, bronchial/visceral sm, eye
M4 - CNS
M5 - CNS

Question 4

What are the features of type 1 nicotinic receptors?

Answer 4

These are FASTER ligand-gated ion-channels (type 1 receptor)

Each receptor is made up of 5 subunits; alpha, beta, gamma, delta, epsilon.

Muscle type: 2 alpha, beta, delta, epsilon.

Ganglion type: 2 alpha, 3 beta.
The subunit combination determines the ligand-binding properties of the receptor.

The effects of ACh are relatively weak on these receptors.

Question 5

What do the different muscarinic receptors do?

Answer 5

M1,3,5 - linked to Gq (excitatory) - PIP2->IP3 +DAG

M2,4 linked to GI (inhibitory) - cAMP

Question 6

Where are muscarinic receptors found?

Answer 6

eye
salivary glands
lungs
sweat glands
heart
gut (smooth muscle)
bladder
vasculature

Question 7

What are the muscarinic effects on the eye?

Answer 7

Cholinergic innervation mediates:

1. Ciliary muscle contraction - near vision (bulges lense)
2. Sphincter pupillae contraction - miosis and drainage of intra-ocular fluid
3. Lacrimation - tears

Glaucoma:
1. Contraction of the sphincter pupillae opens a pathway for aqueous humour, allowing drainage via the Canals of Schlemm thus reducing IOP - in glaucoma this is impeded.

Question 8

What are the muscarinic effects in the heart?

Answer 8

The M2 AChR are located mainly in the atria and the nodes.

• The depressing effect on the heart (GI muscarinic receptors) is mediated by:
  1. Reduction of cAMP.
  2. Decreased Ca2+ entry -> decreased CO. 3.Increased K+ efflux -> decreased HR.

Question 9

What is the muscarinic effect on the vasculature?

Answer 9

MOST blood vessels do NOT have parasymoathetic innervation.

ACh acts on vascular endothelial cells to stimulate NO release via M3 AChR.

NO then acts on vascular smooth muscle and relaxes it (no direct relaxation).

Results in a decreased TPR.

Question 10

What is the muscarinic effect on cardiovascular system?

Answer 10

decreased: HR, CO, vasodilation -> drop in BP

Question 11

What is the muscarinic effect on non- vascular smooth muscle?

Answer 11

SM with PNS innervation CONTRACTS (instead of relax).

Lungs - bronchoconstriction.

Gut - increased peristalsis (motility) - can result in GI pain.

Bladder - Increased bladder emptying.

Question 12

What are the muscarinic effects on the exocrine glands?

Answer 12

• Salivation.
• Increased bronchial and GI secretions (including gastric HCl production).
• Increased sweating.

Question 13

Summarise the muscarinic effects in the body

Answer 13

decreased HR

decreased BP

increased sweating

difficulty breathing

bladder contraction

GI pain

increased salivation and tears

Question 14

What are the directly acting cholinomimetics?

Answer 14

typical agonists at muscarinic receptors :
1. choline esters e.g betanechol

2. alkaloids e.g pilocarpine

Question 15

Describe the actions of bethanechol (choline ester) . What are the side effects?

Answer 15

M3 AChR selective agonist.
Resistant to degradation, orally active, limited access to brain (t1/2 ~ 3-4hrs).

Used to aid bladder emptying and enhance GI motility.

Side effects - blurred vision, sweating, nausea, hypotension, respiratory distress, bradycardia.

Question 16

Decribe the actions of pilocarpine (alkaloid). What are the side effects?

Answer 16

Non-selective (attaches to only muscarinic receptors but any sub-types) muscarinic agonist with good lipid solubility (t1/2 ~ 3-4hrs).

Used to treat glaucoma.

Side effects - blurred vision, sweating, GI pain, hypotension, respiratory distress.

Question 17

What are the indirectly acting cholinomimetic drugs?

Answer 17

increase the effect of normal parasympathetic nerve stimulation
inhibitors of chlinoeasterase enymes

1. reversible e.g physostigmine
2. irreversible e.g ecothipate

Question 18

What are the different types of colinesterases?

Answer 18

increase the effect of normal PNS stimulation.

Cholinesterase enzymes metabolise ACh to choline and acetate, there are 2 types of enzyme:

1. Acetylcholinesterase (true or specific).
   - Found in SYNAPSES.
   - RAPID action.
   - Highly selective for ACh.
2. Butyrylcholinesterase (pseudo).
   - Found in plasma and most tissues but NOT in synapses.
   - Broad substrate specificity.
   - Is the principal reason for low plasma ACh.
   - Shows genetic variation.

Question 19

What are the effects of cholinesterase inhibitors?

Answer 19

low dose - enhanced muscarinic activity.

Moderate dose - further enhancement, increased transmission at ALL ANS ganglia (Inc. nAChRs).

High doses - TOXIC - depolarising block t autonomic ganglia and NMJ

Question 20

How do reversible anticholinesterases work?

Answer 20

Physostigmine, neostigmine, donepezil.

They donate a carbamyl group to the enzyme active site, blocking the active site (competitive).

The carbamyl group is then removed via SLOW hydrolysis (minutes).

Physostigmine - a tertiary amine, acts at the postganglionic PNS synapse.

Used to treat glaucoma (aids IOP reduction) and atropine poisoning (particulary in children)

Question 21

How do irreversible anticholinesterases work?

Answer 21

Ecothiopate, dyflos, sarin (all organophosphate compounds).

Rapidly react to enzyme active site and leave a large blocking group – stable and resistant to hydrolysis.

Ecothiopate - a potent inhibitor of acetylcholinesterases.

Slow reactivation of the enzyme takes several days.

Used to treat glaucoma (eye drops) with a prolonged duration of action.

Side effects - sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty.

Question 22

What are the effects of anticholinesterase drugs on the CNS?

Answer 22

Non-polar anticholinesterases can cross the blood brain barrier(e.g. physostigmine).
- Low doses - excitation with possibility of convulsions.

High doses - unconsciousness, respiratory depression, death

Question 23

What is the treatment for organophosphate poisoning?

Answer 23

Severe toxicity is caused by accidental exposure to organophosphates used in insecticides/nerve gas.

Treatment = IV atropine, artificial respiration, IV pralidoxime.

The phosphorylated enzyme ‘ages’ within a few hours - just keep them alive until then.

Pralidoxime can cause anticholinesterases to unbind.