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LCRS Pharmacology and Therapeutics > Cholinomimetics > Flashcards

Cholinomimetics Flashcards

1
Q

What are cholinomimetics?

A

Drugs that mimic the action of acetylcholine in the body- parasympathomimetic drugs

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2
Q

How is acetylcholine synthesised?

A

From acetyl coA and choline by choline acetyltransferase (CAT)

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3
Q

What causes the exocytosis of Ach?

A

Depolarisation causes opening of voltage sensitive calcium channels and influx of calcium causes exocytosis of Ach

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4
Q

What is Ach broken down by?

A

Acetylcholinesterase

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5
Q

What is the most common muscarinic antagonist?

A

Atropine

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6
Q

What do muscarinic actions correspond to?

A

Parasympathetic stimulation

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7
Q

After atropine blockade of muscarinic actions, what do larger doses of acetylcholine induce?

A

Effects similar to those caused by nicotine

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8
Q

What are the three main muscarinic receptor subtypes?

A

M1- CNS excitation, salivary glands, stomach (release of HCl)
M2- Heart (decreases rate)
M3- Salivary glands, bronchial/visceral smooth muscle, sweat glands and eye

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9
Q

Where are M4 and M5?

A

In the CNS

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10
Q

What effect do muscarinic receptors normally have?

A

Excitatory

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11
Q

What is the exception to muscarinic receptors’ excitatory effect?

A

M2 receptors in the heart are inhibitory

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12
Q

What sort of receptors are muscarinic receptors?

A

Type 2 receptors (G protein coupled)

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13
Q

Which muscarinic receptors are Gq protein linked receptors?

A

M1, M3 and M5 (odds)

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14
Q

What sort of receptor are M2 and M4 (evens)?

A

Gi protein linked receptors

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15
Q

What do Gq protein receptors stimulate when bound to?

A

They stimulate PLC to increase production of IP3 and DAG

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16
Q

What do Gi protein receptors stimulate when bound to?

A

Inhibitory- reduces production of cAMP

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17
Q

What sort of receptor are nicotinic receptors?

A

Ligand gated ion channels

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18
Q

What are the 5 subunits the can make up the nicotinic receptor?

A

Alpha, beta, gamma, delta and epsilon

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19
Q

What do the subunits in the receptor determine?

A

Ligand binding properties of the receptor

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20
Q

What are the 2 main types of nicotinic receptor?

A

In the muscle= 2 alpha + beta + delta + epsilon

In the ganglion= 2 alpha + 3 beta

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21
Q

How does the effect of acetylcholine on nicotinic receptors compare to on muscarinic receptors?

A

Relatively weak

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22
Q

What are the three main muscarinic effects on the eye?

A

Contraction of the ciliary muscle (accommodates for near vision)
Contraction of sphincter pupillae (circular muscle of the iris)
Lacrimation

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23
Q

What does constriction of the sphincter pupillae do?

A

Constricts the pupil (mitosis) and increases drainage of intraocular fluid

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24
Q

What is glaucoma?

A

Increase in intraocular pressure

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25
Q

Why is glaucoma harmful?

A

It can damage the optic nerves and retina and it can ultimately lead to blindness

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26
Q

What generates aqueous humour?

A

Capillaries of the ciliary body

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27
Q

Where does aqueous humour go after being generated?

A

Anterior chamber of the eye

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28
Q

What is the role of the aqueous humour?

A

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

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29
Q

How does aqueous humour drain back into the venous system?

A

Through the canals of Schlemm

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30
Q

What is angle-closure glaucoma?

A

The angle between the cornea and the iris becomes narrowed- this reduces the drainage of the intraocular fluid via the canals of schlemm so intraocular pressure increases

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31
Q

What happens to patients with angle closure glaucoma when given a muscarinic agonist?

A

The iris contracts which opens up the angle and increases the drainage of intraocular fluid through the canals of Schlemm

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32
Q

How do muscarinic receptors have an inhibitory effect on the heart?

A

They decrease cAMP activity which leads to decreased Ca2+ entry which causes decreased cardiac output and increased K+ efflux which leads to decreased heart rate

33
Q

Where are M2 receptors found in the heart?

A

In the atria and both nodes

34
Q

What is parasympathetic control of blood vessels like?

A

Most blood vessels don’t have parasympathetic innervation but have receptors

35
Q

How does acetylcholine act on vasculature?

A

It acts on vascular endothelial cells to stimulate NO release via M3 receptors which induces vascular smooth muscle relaxation which causes a decrease in TPR

36
Q

What is the muscarinic effect on non-vascular smooth muscle that has parasympathetic innervation?

A

Opposite effect to vascular smooth muscle- it contracts
Lungs- constriction
Gut- increased peristalsis/motility
Bladder- increased bladder emptying

37
Q

What is the muscarinic effects on exocrine glands?

A

Salivation
Increased bronchial secretions
Increased GI secretions
Increased sweating

38
Q

What are the two types of cholinomimetic?

A 
Directly acting (muscarinic receptor agonists)
Indirectly acting
39
Q

What are the two types of muscarinic receptor agonist?

A 
Choline esters (bethanechol)
Alkaloids (pilocarpine)
40
Q

Why is pilocarpine a non-selective muscarinic agonist?

A

It has a some structural similarity to acetylcholine so it can stimulate all muscarinic receptors

41
Q

What is the half life of pilocarpine?

A

3-4 hours

42
Q

What is pilocarpine often used as a treatment for?

A

Glaucoma (constricts sphincter pupillae)

43
Q

What are the side effects of pilocarpine use?

A 
General effects of parasympathetic discharge:
Blurred vision
Sweating
GI disturbance and pain
Hypotension
Respiratory distress
44
Q

What sort of agonist is bethanechol due to its structure?

A

Its structure is only very slightly different to acetylcholine in terms of structure so it is an M3 receptor selective agonist

45
Q

What effect does acetylcholinesterase have on bethanechol?

A

None because it is highly resistant to degradation by acetylcholinesterase

46
Q

What is the half life on bethanechol?

A

3-4 hours

47
Q

What is bethanechol mainly used for?

A

Assist bladder emptying and enhance gastric motility

48
Q

What are the side effects of bethanecol?

A

Same as pilocarpine- parasympathetic discharge

49
Q

What do indirectly acting cholinomimetic drugs do?

A

They inhibit acetylcholinesterase

50
Q

How does inhibiting acetylcholinesterase lead to a cholinomimetic effect?

A

It increases the amount of acetylcholine in the synapse and by doing this, they increase the effect of normal parasympathetic stimulation

51
Q

Give some examples of reversible anticholinesterases?

A

Physostigmine
Neostigmine
Donepezil

52
Q

Give some examples of irreversible anticholinesterases?

A

Ecothiopate
Dyflos
Sarin

53
Q

What are the two types of cholinesterase?

A

Acetylcholinesterase (true cholinesterase)

Butyrylcholinesterase (pseudocholinesterase)

54
Q

Where is acetylcholinesterase found?

A

All cholinergic synapses

55
Q

How fast to act is acetylcholinesterase?

A

Very rapid (>10000 reactions per second)

56
Q

Where is butyrylcholinesterase found?

A

In plasma and most tissues but not in cholinergic synapses

57
Q

How does the specificity of butyrylcholinesterase compare to acetylcholinesterase?

A

Acetylcholinesterase is highly specific for acetylcholine but butyrylcholinesterase has a broad substrate specificity- hydrolyses other esters e.g. suxamethonium

58
Q

What does the broad specificity of butyrylcholinesterase mean that it is the principal reason for?

A

Low plasma acetylcholine

59
Q

What is the effect of cholinesterase inhibitors in low doses?

A

Enhanced muscarinic activity

60
Q

What is the effect of cholinesterase inhibitors in moderate doses?

A

Further enhanced muscarinic activity

Increased transmission at all autonomic ganglia- Ach conc will increase at all

61
Q

What is the effect of cholinesterase inhibitors in high doses?

A

There is a depolarising block at the autonomic ganglia and neuromuscular junction- nicotinic receptors get overstimulated so shut down

62
Q

How do reversible anti cholinesterase drugs like physostigmine and neostigmine work?

A

They compete with acetylcholine for the active site on acetylcholinesterase- they donate a carbamyl group to the enzyme blocking the active site

63
Q

How are carbamyl groups removed from the active sites?

A

Slow hydrolysis which takes minutes and this increases duration of acetylcholine activity in synapse

64
Q

Where does physostigmine primarily act?

A

Postganglionic parasympathetic synapse

65
Q

What is the half life of physostigmine?

A

30 mins

66
Q

What is physostigmine used to treat?

A

Glaucoma- increases drainage of intraocular fluid

Atropine poisoning

67
Q

How is physostigmine treat atropine poisoning?

A

Atropine is a competitive muscarinic antagonist meaning that it is surmountable, physostigmine increases the concentration of Ach at the synapse so that it can outcompete atropine

68
Q

What sort of compounds are irreversible anticholinesterase drugs?

A

Organophosphate compounds

69
Q

How do irreversible anti cholinesterase drugs work?

A

They rapidly react with the enzyme active site, leaving a large blocking group which is stable and resistant to hydrolysis so recovery requires production of new enzymes which takes days/weeks

70
Q

What is the only irreversible anti-cholinesterase drug in clinical use?

A

Ecothiopate

71
Q

What is ecothiopate used to treat?

A

Glaucoma

72
Q

How can anticholinesterase drugs reach the CNS to have an effect?

A

If they are non-polar they can cross the blood brain barrier

73
Q

If low doses of anticholinesterase drugs reach the CNS, what effect do they have?

A

CNS excitation with possibility of convulsions

74
Q

If high doses of anticholinesterase drugs reach the CNS, what effect do they have?

A

Unconsciousness, respiratory depression and death

75
Q

What anticholinesterases are used to treat Alzheimer’s?

A

Donepezil and tacrine

76
Q

What brain functions is acetylcholine important in?

A

Learning and memory

77
Q

Why are organophosphates poisonous?

A

They cause an increase in muscarinic activity which leads to CNS excitation which leads to depolarising NM block

78
Q

How do you treat organophosphate poisoning?

A

IV atropine
Respirator
If found in first few hours give pralidoxime (IV)

LCRS Pharmacology and Therapeutics (33 decks)

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