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Y2 LCRS Pharm Fwong > 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 Nicotinic effects are those that an be replicated by nicotine Comes from amanita muscaria and nicotiana tabacum

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3
Q

What can be given to abolish muscarinic effects?

A

Atropine (competitive muscarinic antagonist)

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4
Q

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

A

M1 – MOne “moan”= acid reflux so stomach (gastric acid secretion/ “heart burn” due to acid reflux) Other effects - salivary glands, CNS.

M2 – heart

M3 – mainly parasympathetic effects: salivary glands, bronchial smooth muscle constriction, visceral smooth muscle (constriction for GI motility), eyes (constriction pupil), VASODILATION (stimulates NO release) and sweat glands etc.

M4 and M5 are found in the CNS NOTE: muscarinic receptors are generally excitatory except for on the heart

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5
Q

What type of receptor are muscarinic,nicotinic and adrenergic receptors?

A

Muscarinic receptors (ACh) = G protein coupled

Nicotinic (ACh)= ionotropic

Adrenergic (NA)= G protein coupled

These are the 3 main receptors of the autonomic Nervous system

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6
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 convertes PIP2 to IP3 and DAG

M2 and M4 = Gi protein linked receptors (inhibitory) – they decrease the production of cAMP

IP3 (inositol triphosphate) pathway leads to Ca2+ release. You can remember this because M3 leads to a lot of parasympathetic effects like bronchiole smooth muscle contraction etc

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7
Q

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

A

Nicotinic receptors consist of 5 subunits (either alpha, beta, gamma, delta or epsilon) The combination of subunits determines its ligand binding properties.

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8
Q

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

A

Muscle and Ganglion

Muscle = 2 alpha + beta + delta + epsilon

Ganglion = 2 alpha + 3 beta

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9
Q

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

A

The effects of acetylcholine are relatively weak on nicotinic compared to muscarinic

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10
Q

What three effects does muscarinic stimulation have on the eye?

A
  1. Contraction of the ciliary muscle (accommodate for near vision), but also opens up trabecular meshwork for aqueous humour drainage (good for glaucoma)
  2. Constriction of sphincter pupillae (circular muscle of the eye) – this constricts the pupil and moves iris away from canal of schlemm, improving drainage of intraocular fluid (good for glaucoma)
  3. Lacrimation

note muscarinic receptors = parasympathetic NS

adrenergic receptors= sympathetic NS

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11
Q

What is glaucoma?

A

Sustained raised intraocular pressure – this can cause damage to the optic nerves and retina and can lead to blindness

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12
Q

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

A

The capillaries in the ciliary body produce aqueous humour Aqueous humour passes anteriorly into the anterior chamber and is then drained through the canals of Schlemm into the venous system

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13
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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14
Q

What happens in Angle-closure glaucoma?

A

The angle between the cornea and the iris is narrowed which decreases the drainage of intraocular fluid through the canals of Schlemm

see slide 11

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15
Q

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

A

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

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16
Q

Describe, in detail (including the mechanism), the muscarinic effects on the heart.

A

Binding of acetylcholine to the M2 receptors (Gi protein linked receptor) causes a decrease in cAMP production.

This triggers

  1. a decrease in Ca2+ influx, which leads to a decrease in cardiac output (less contractility)
  2. It also triggers an increase in K+ efflux, which leads to a decrease in heart rate (resting membrane potential more negative)

NB heart parasympathetic innervation= vagus

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17
Q

Describe the muscarinic effects on the vasculature.

A

There is no direct parasympathetic innervation of blood vessels However, there are muscarinic receptors on the endothelial cells When stimulated, it triggers the production of nitric oxide (NO) from the endothelial cells, which causes vasodilation and a decrease in TPR

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18
Q

Summarise the muscarinic effects on the cardiovascular system.

A

Decrease in heart rate

Decreased stroke volume (decreased atrial contraction, if less blood moves from atria to ventricle the stroke volume will decrease as well)

= DECREASED CO

Decrease in total peripheral resistance (due to vasodilation)

=OVERALL DECREASED BP

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19
Q

Describe the muscarinic effects on non-vascular smooth muscle.

A

It is the opposite of muscarinic effects on vascular smooth muscle

It causes CONTRACTION of non-vascular smooth muscle

Lungs – bronchoconstriction

GI tract – increased motility

Bladder – increased bladder emptying

20
Q

Describe the muscarinic effects on exocrine glands.

A

Salivation

Increased bronchial secretions

Increased GI secretions (including gastric HCl production)

Increased sweating (sympathetic-mediated)

21
Q

What are the two types of cholinomimetic drug?

A

Directly Acting – muscarinic agonists

Indirectly Acting – acetylcholinesterase inhibitors -> increase the synaptic concentration of acetylcholine

22
Q

State two types of muscarinic receptor agonists (ie give the two types of directly acting cholinomimetics) and give an example of each.

A

Choline Esters – Bethanechol Alkaloids - Pilocarpine

23
Q

Describe the selectivity of pilocarpine.

A

Non-selective muscarinic receptor agonist (muscarinic>nicotinic)

It stimulates ALL muscarinic receptors.

24
Q

What is pilocarpine used to treat?

A

glaucoma

25
Q

State some side-effects of pilocarpine.

A

Blurred vision

Hypotension

Sweating

Respiratory difficulty

GI disturbance and pain

remember that muscarinic causes CONTRACTION on NON VASCULAR muscles, including bronchial smooth muscles, GI tract smooth muscles etc leading to bronchoconstrction and hence respiratory difficulty mentioned above. (see card 19)

26
Q

Describe the selectivity of bethanechol.

A

M3 selective agonist

27
Q

Clinical uses of bethanechol

A

Assist bladder emptying

Enhance gastric motility

28
Q

State some side-effects of bethanechol.

A

Same as pilocarpine + bradycardia, nausea

sweating, impaired vision, bradycardia, hypotension, respiratory difficulty, nausea

29
Q

What is the half-life of pilocarpine and bethanechol?

A

3-4 hours

30
Q

What are the two types of anticholinesterase (ie indirectly acting cholinomimetic drugs)? Give examples of each.

A

Reversible – physostigmine, neostigmine, donepezil Irreversible – ecothiopate, dyflos, sarin

31
Q

What are the two types of cholinesterase?

A

Acetylcholinesterase Butyrylcholinesterase

32
Q

Compare the two cholinesterases

A

Location:

AChE: ALL cholinergic synapses

BChE: Plasma and most tissues NOT cholinergic synapses

Speed:

AChE has very RAPID action, probably quicker than BChE

Substrate specificity:

AChE: HIGHLY SELECTIVE for acetylcholine

BChE: Broad specificity- hydrolyses other substrates in addition to AChE eg suxamethonium

33
Q

Where is butyrylcholinesterase found? Describe its properties

A

Butyrylcholinesterase is found in plasma and most tissues but NOT in cholinergic synapses It has a broad substrate specificity – it hydrolyses other esters e.g. suxamethonium It shows genetic variation

34
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 (nicotinic receptors) because it starts to affect the synapses which uses nicotinic AChreceptors

HIGH – depolarising block at autonomic ganglia and NMJ (the nicotinic receptors get overstimulated so they shut down). THIS IS BAD IF IT IS RESPIRATORY MUSCLE

35
Q

Describe the mechanism of action of reversible anticholinesterases.

A

Reversible anticholinesterases donate a CARBAMYL group, which blocks the active site of the acetylcholinesterase Carbamyl groups are removed by slow hydrolysis (takes mins rather than miliseconds)

36
Q

Which synapses does pilocarpine primarily act on?

A

Postganglionic parasympathetic synapses (muscarinic cholinergic synapses)

37
Q

What is physostigmine used to treat?

A

Glaucoma

atropine poisoning

38
Q

What is the half-life of physostigmine?

A

30 mins

39
Q

What type of poisoning is physostigmine used to treat?

A

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

40
Q

What type of compound are irreversible anticholinesterases?

A

Organophosphates

41
Q

Describe the mechanism of action of irreversible anticholinesterases.

A

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

42
Q

What is ecothiopate used to treat? What is special about its duration of action?

A

Glaucoma, acts to increase aqueuous humour drainage. Has a prolonged effect (since it is an irreversiible inhibitor)

43
Q

State some side-effects of ecothiopate.

A

Blurred vision

Sweating

Respiratory difficulty

Hypotension

GI disturbance and pain

Bradycardia

ie symptoms of too much muscarinic stimulation

44
Q

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

A

Non-polar

45
Q

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

A

Low – CNS excitation with the possibility of convulsions

High – unconsciousness, respiratory depression and death

46
Q

Describe the treatment of organophosphate poisoning.

A

Organophosphates are irreversible anticholinesterases.

IV atropine – this blocks the muscarinic receptors thus reducing the effect of the raised synaptic acetylcholine concentration Patient is put on artificial ventilation because of the respiratory depression caused by the excess acetylcholine at the NMJ of respiratory muscles (causing a depolarising block)

If found within the first few hours, the patient should be given IV PRALIDOXIME, which can unblock the AChE from organophosphates

Y2 LCRS Pharm Fwong (40 decks)

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