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YR2 LCRS Pharm > Cholinomimetics > Flashcards

Cholinomimetics Flashcards

1
Q

Describe the synthesis of acetylcholine.

A

Acetylcholine is synthesised from Acetyl CoA and choline via choline acetyltransferase (CAT)

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2
Q

Why are the receptors described as nicotinic and muscarinic?

A

Muscarinic effects are those that can be replicated by muscarine + abolished by atropine. Correspond to parasympathetic stimulation.
Nicotinic effects are those that an be replicated by nicotine

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3
Q

State where you would find the different types of muscarinic receptor.

A

M1: salivary glands, CNS, stomach
M2: heart
M3: salivary glands, bronchial/ visceral smooth muscle, eyes, + sweat glands
M4 and M5 are found in the CNS
NOTE: generally excitatory except for on the heart

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4
Q

What type of receptor are all muscarinic receptors?

A

G-protein coupled receptors

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5
Q

What is the difference in the G-protein receptors of M1, M3 and M5 compared to M2 and M4?

A

M1, M3 and M5 = Gq protein linked receptors: they stimulate PLC which increases IP3 and DAG
M2 and M4 = Gi protein linked receptors (inhibitory) – they decrease the production of cAMP

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6
Q

Describe the structure of nicotinic receptors. What determines its ligand binding properties?

A

Ligand gated ion channels- consist of 5 subunits (alpha, beta, gamma, delta or epsilon)
Combination of subunits determines ligand binding properties.

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7
Q

What are the 2 main types of nicotinic receptor? Describe their subunit composition.

A 
Muscle = 2 alpha + beta + delta + epsilon 
Ganglion = 2 alpha + 3 beta
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8
Q

How do the effects of acetylcholine on nicotinic receptors compare to its effects on muscarinic receptors?

A

Effects of ACh are relatively weak on nicotinic compared to muscarinic

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9
Q

What 3 effects does muscarinic stimulation have on the eye?

A

Contraction of the ciliary muscle (accommodates near vision)
Constriction of sphincter pupillae (circular muscle of iris) – this constricts the pupil + increases drainage of intraocular fluid
Lacrimation

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10
Q

What is glaucoma?

A

Sustained raised intraocular pressure
Can cause damage to the optic nerves + retina
Can lead to blindness

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11
Q

Where is aqueous humour produced? Describe its passage through the eye.

A

Capillaries in the ciliary body produce aqueous humour
which flows anteriorly into the anterior chamber and is then drained through the canals of Schlemm into the venous system

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12
Q

What is the role of aqueous humour?

A

Provides oxygen and nutrients to the cornea and lens because they don’t have a blood supply

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13
Q

What happens in Angle-closure glaucoma?

A

Angle between cornea + iris is narrowed, which decreases the drainage of intraocular fluid through the canals of Schlemm, thus intraocular pressure increases

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14
Q

What are the effects of giving a muscarinic agonist to people with Angle-closure glaucoma?

A

Causes constriction of sphincter pupillae and opens up the angle to increase the drainage of intraocular fluid

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15
Q

Describe the muscarinic effects on the heart.

A

Binding of ACh to M2 receptors causes a decrease in cAMP production
This triggers a decrease in Ca2+ influx, which leads to a decrease in CO
It also triggers an increase in K+ efflux, which leads to a decrease in HR

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16
Q

Describe the muscarinic effects on the vasculature.

A

No direct parasympathetic innervation of blood vessels
However, there are muscarinic receptors on the endothelial cells
ACh stimulates production of NO from the endothelial cells, which causes vasodilation and a decrease in TPR and BP

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17
Q

Summarise the muscarinic effects on the cardiovascular system.

A

Decrease in HR
Decrease in CO (due to decreased atrial contraction)
Decrease in TPR (due to vasodilation)
Decrease in BP

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18
Q

Describe the muscarinic effects on non-vascular smooth muscle.

A

Opposite of muscarinic effects on vascular smooth muscle
It causes CONTRACTION of non-vascular smooth muscle
Lungs = bronchoconstriction (difficulty breathing)
GI tract = increased motility (GI pain)
Bladder = increased bladder emptying

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19
Q

Describe the muscarinic effects on exocrine glands.

A

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

20
Q

What are the 2 types of cholinomimetic drug?

A

Directly Acting: muscarinic agonists

Indirectly Acting: acetylcholinesterase inhibitors -> increase the synaptic concentration of ACh

21
Q

State 2 types of muscarinic receptor agonists and give an example of each.

A

Choline Esters e.g. Bethanechol

Alkaloids e.g. Pilocarpine

22
Q

Describe the selectivity of pilocarpine.

A

Non-selective muscarinic receptor agonist

It stimulates ALL muscarinic receptors

23
Q

What is pilocarpine used to treat?

A

Glaucoma (stimulates muscarinic receptors of iris, flattening iris + improving drainage)

24
Q

State 5 side-effects of pilocarpine.

A 
Blurred vision  
Hypotension 
Sweating  
Respiratory difficulty  
GI disturbance and pain
25
Q

Describe the selectivity of bethanechol.

A

M3 selective agonist

26
Q

What are the effects of bethanechol?

A

Assist bladder emptying

Enhanced gastric motility

27
Q

State some side-effects of bethanechol.

A

Same as pilocarpine + bradycardia

Higher incidence of side effects as systemic (oral)

28
Q

What is the half-life of pilocarpine and bethanechol?

A

3-4 hours

29
Q

What are the 2 types of anticholinesterase? Give examples of each.

A

Reversible e.g. physostigmine, neostigmine, donepezil

Irreversible e.g. ecothiopate, dyflos, sarin

30
Q

What are the 2 types of cholinesterase? What do they do?

A

Acetylcholinesterase
Butyrylcholinesterase
Metabolise ACh to choline and acetate

31
Q

Where is acetylcholinesterase found? Describe its properties.

A

Found in ALL cholinergic synapses

Has very RAPID action and it is HIGHLY SELECTIVE for ACh

32
Q

Where is butyrylcholinesterase found? Describe its properties

A

Found in plasma and most tissues but NOT cholinergic synapses
Has a broad substrate specificity – it hydrolyses other esters e.g. suxamethonium
Is principle reason for low plasma ACh
It shows genetic variation

33
Q

State the effects of low, moderate and high doses of cholinesterase inhibitors.

A

LOW: enhances muscarinic effects
MODERATE: further enhances muscarinic effects + increases transmission at ALL autonomic ganglia (nAChRs)
HIGH: depolarising block at autonomic ganglia + NMJ (nicotinic receptors get overstimulated so they shut down)

34
Q

Describe the mechanism of action of reversible anticholinesterases.

A

Compete with ACh for active site on cholinesterase enzyme
Donate a CARBAMYL group, which blocks the active site + prevents ACh from binding
Carbamyl groups are removed by slow hydrolysis (mins rather than miliseconds)
Increase duration of ACh activity in synapse

35
Q

What is physostigmine used to treat?

A

Glaucoma- improves muscarinic response in eye, aiding intraocular fluid drainage

36
Q

What is the half-life of physostigmine?

A

30 mins

37
Q

What type of poisoning is physostigmine used to treat?

A

Atropine poisoning ( it increases the synaptic concentration of ACh so it can outcompete the atropine)

38
Q

What type of compound are irreversible anticholinesterases?

A

Organophosphates

39
Q

Describe the mechanism of action of irreversible anticholinesterases.

A

Rapidly react with enzyme active site, leaving a large blocking group
Bocking group is stable + resistant to hydrolysis so recovery requires production of new enzymes

40
Q

What is ecothiopate used to treat?

A

Glaucoma

41
Q

State some side-effects of ecothiopate.

A 
Blurred vision  
Sweating  
Respiratory difficulty  
Hypotension 
GI disturbance and pain  
Bradycardia
42
Q

What type of anticholinesterases can cross the blood-brain barrier? Give an example

A

Non-polar

e.g. physostigmine

43
Q

Describe the effects of low and high doses of anticholinesterase drugs on CNS activity.

A

Low: Excitation with possibility of convulsions
High: unconsciousness, respiratory depression + death

44
Q

Describe the treatment of organophosphate poisoning.

A

IV atropine: blocks the muscarinic receptors thus reducing the effect of the raised synaptic ACh concentration
Patient is put on a respiratory because of respiratory depression caused by excess ACh at the synapse (causing a depolarising block)
If found within the first few hours, the patient should be given IV PRALIDOXIME, which can unblock the enzymes

45
Q

Where is the primary site of action of physostigmine?

A

Postganglionic parasympathetic synapse

46
Q

What are other organophosphates commonly used as?

A

Insecticides

47
Q

What is ecothiopate a potent inhibitor of?

A

Acetylcholinesterase

YR2 LCRS Pharm (34 decks)

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