Cholinomimetics Flashcards
(97 cards)
1
Q
What are cholinomimetics
A
Drugs that mimic the action of ACh
2
Q
what is the reuptake mechanism of ACh
A
It doesn’t get reuptaken
3
Q
Describe the synthesis, excretion, metabolism of ACh
A
Acetyl CoA and choline is converted to ACh and CoA. ACh is packaged into vesicles and secreted upon the arrival of an action potential. in the synapse it activates its receptor and then is broken down into choline and acetate by acetylcholinesterase
4
Q
What enzyme breaks down ACh and what are the products
A
Acetylcholinesterase, choline and acetate
5
Q
What is ACh synthesised from
A
Choline and acetyl CoA
6
Q
What enzyme synthesises ACh, what’s the other product
A
choline acetyltransferase, CoA
7
Q
What types of receptor ACh stimulate, nicotinic or muscarinic
A
Both
8
Q
What drug is commonly used as a muscarinic antagonist
A
atropine
9
Q
which branch of the NS corresponds with muscarinic stimulation
A
parasympathetic
10
Q
what can happen if you administer a large dose of ACh after using atropine
A
you stimulate nicotinic receptors
11
Q
Which muscarinic receptors are excitatory vs inhibitory
A
All 5 except M2 on the heart are excitatory
12
Q
where are M2 receptors found
A
Heart
13
Q
Where are M1 receptors found (3)
A
salivary glands, stomach and CNS
14
Q
Where are M3 receptors found (4)
A
Salivary glands, bronchial/visceral smooth muscle, sweat glands, eye
15
Q
What types of muscarinic receptors are found at: Salivary glands, bronchial/visceral smooth muscle, sweat glands, eye
A
M3
16
Q
What types of muscarinic receptors are found at: the heart
A
M2
17
Q
What types of muscarinic receptors are found at: salivary glands, stomach and CNS
A
M1
18
Q
What are special about M2 receptors
A
Inhibitory
19
Q
What are special about the hearts muscarinic receptors
A
Inhibitory
20
Q
Where are M4 receptors found
A
CNS
21
Q
Where are M5 receptors found
A
CNS
22
Q
What type of receptor are muscarinic receptors
A
Type 2 G protein couples
23
Q
What type of G protein receptors are M1, 3 and 5
A
Gq proteins linked to IP3 and DAG
24
Q
What type of G protein receptors are M2 and 4
A
Gi proteins and linked to cAMP
25
Which muscarinic receptors are Gq proteins
M1, 3 and 5
26
Which muscarinic receptors are Gi proteins
M2 and 4
27
Which muscarinic receptors are IP3 and DAG linked
1, 3 and 5
28
Which muscarinic receptors are linked to cAMP
2 and 4
29
cAMP is which type of G protein?
Gi
30
IP3 and DAG is which type of G protein?
Gq
31
Gq protein uses which second messenger?
IP3 and DAG
32
Gi protein uses which second messenger?
cAMP
33
What type of receptors are nicotinic receptors?
Type 1 gated ion channels
34
Which types of muscarinic receptor is found in the CNS
1, 4 and 5
35
How many subunits on a nicotinic receptor and what are they called?
5 subunits, known as alpha beta gamma delta and epsilon
36
What determines the ligand binding properties of a nicotinic receptor
the subunit combination
37
Which branch of the NS uses nicotinic receptors
Both
38
What is the subunit combination of nicotinic receptors in muscle
2alpha, beta, delta, epsilon
39
What is the subunit combination of nicotinic receptors in ganglions
2alpha 3beta
40
2alpha 3beta is the nicotinic subunit combination for where
ganglions
41
2alpha, beta, delta, epsilon is the nicotinic subunit combination for where
Muscle
42
Where are ACh effects more potent, muscarinic or nicotinic receptors
Muscarinic
43
What type of muscarinic receptors are found in the eye
M3
44
What does contraction of the sphincter pupillae do
constricts the pupil and improves drainage of intraocular fluid by opening up pathway for aqueous humour, allowing the Canal of Schlemm to drain aqueous humour and reducing intraocular pressure
45
What does contraction of the ciliary muscle do
Accommodates for near vision by bulging the pupil
46
What're the muscarinic effects of the eye (3)
Contraction of the sphincter pupillae, ciliary muscle and lacrimation
47
How does stimulation of the muscarinic receptor reduce intraocular pressure
Opening up the pathway for aqueous humour and allowing drainage via the canals of Schlemm
48
What effect does muscarinic stimulation have on the heart
reduction in cAMP and decreased cardiac output and heart rate
49
What effects does muscarinic stimulation have on smooth muscle
Stimulates NO release which induces vascular smooth muscle relaxation leading to a lower TPR
50
What effects does muscarinic stimulation have on the CVS system
Decreased heart rate (M2) (bradycardia).
Decreased cardiac output (due to decreased atrial contraction).
Vasodilation (stimulation of NO production).
All of this combined leads to a sharp drop in BP.
51
What effects does muscarinic stimulation have on non-vascular smooth muscle (3)
Lung: bronchoconstriction.
Gut: increased peristalsis (motility).
Bladder: increased bladder emptying
52
What effects does muscarinic stimulation have on the exocrine glands
Salivation.
Increased bronchial secretions.
Increased gastro-intestinal secretions (including gastric HCl production).
Increased sweating (SNS-mediated).
53
Summarise the effects of muscarinic stimulation (7)
```
Decreased heart rate.
Decreased blood pressure.
Increased sweating.
Difficulty breathing.
Bladder contraction.
Gastrointestinal pain.
Increased salivation and tears
```
54
Where are M2 receptors found in the heart
Atria and nodes
55
What type of muscarinic receptor is found on vascular endothelial cells
M3
56
Does the vasculature have a direct parasympathetic stimulation?
No
57
How does muscarinic stimulation result in a lower blood pressure
ACh acts on vascular endothelial cells to stimulate NO release via M3 AChR.
NO induces vascular smooth muscle relaxation, resulting in a decrease in TPR.
58
What is the difference in reaction to muscarinic stimulation by vascular and non-muscular smooth muscle
Smooth muscle that does have parasympathetic innervation responds in the opposite way to vascular muscle – it contracts
59
2 types of cholinomimetics
Choline esters and alkaloids
60
Example of a choline ester?
Bethanechol
61
Example of an alkaloid?
Pilocarpine
62
Give an example of a selective M3 agonist
Bethanechol
63
Metabolism of bethanechol?
Resistant to degradation as it is not broken down by AChesterase, half-life of 3/4 hours
64
What does bethanechol act on
M3
65
Side effects of bethanechol (5)
sweating, impaired vision, bradycardia, hypotension and respiratory difficulty
66
Give an example of a non-selective muscarinic agonist
Pilocarpine
67
what is betanechol used for
To assist bladder emptying and gastric motility
68
How much access to the brain does bethanechol have and why
Limited as it is not lipid soluble
69
How lipid soluble is bethanechol
Not very
70
How lipid soluble is pilocarpine
Good lipid solubility
71
Half life of pilocarpine?
3/4 hours
72
What is the use of pilocarpine? Why is this what it is ideal for
Local treatment for glaucoma, its lipid solubility allows it to readily pass through the cornea
73
side effects of pilocarpine? (6)
Blurred vision, sweating, gastro-intestinal disturbance and pain, hypotension, respiratory distress
74
Two types of cholinesterase enzymes?
Acetylcholinesterase and butyrylcholinesterase
75
Where is AChesterase found
All cholinergic synapses
76
What is the speed and selectivity of AChesterase
Very rapid and highly selective for ACh
77
Where is butyrylcholinesterase found
In plasma and most tissues but not cholinergic synapses
78
what is specificity of butyrylcholinesterase
Broad specificity so it hydrolyses other esters
79
What is the main reason for a low plasma ACh
Butyrylesterase
80
What are the 2 types of anticholinesterases
Reversible and irreversible
81
What is bethanechol an example of (2)
Choline ester, selective M3 agonist
82
What is pilocarpine an example of (2)
Alkaloid, non-selective muscarinic agonist
83
Example of a reversible anticholinesterase
Physostigmine
84
Example of an irreversible anticholinesterase
Ecothiopate
85
What does a low dose of an anticholinesterase do
Enhanced muscarinic activity
86
What does a moderate dose of anticholinesterase do (2)
Further enhanced msucarinic activity and increased transmission at all autonomic ganglia
87
What does high dose of anticholinesterase do
Toxic, depolarising block at all autonomic ganglia and NMJ
88
How does a reversible anticholinesterase work
Competes with ACh for active site of the cholinesterase. They donate a carbamyl group to the enzyme, blocking the active site and preventing ACh from binding. The carbamyl group is removed by slow hydrolysis (mins rather than msecs) and this increases the duration of ACh activity in the synapse
89
What is physostigmine an example of
Reversible anticholinesterase
90
What is ecothiopate an example of
Irreversible anticholinesterase
91
How does an irreversible anti cholinesterase work
organophosphate compounds. They rapidly phosphorylate the enzyme active site, leaving a large blocking group. This is stable and resistant to hydrolysis, meaning recovery may take weeks as it is mostly done with the production of new enzymes. An example is ecothiopate
92
What is physostigmine used for
acts at the postganglionic parasympathetic synapse and has a half life of around 30 mins. It is used in the treatment of glaucoma and helps to drain intraocular fluid. It can also be used to treat atropine poisoning.
93
What is ecothiopate used for
Used as eye drops in the treatment of glaucoma, acting to increase intraocular fluid drainage with a prolonged duration of action
94
What must be considered when using non-polar anticholinesterases
Effect on the CNS as they can cross the BBB.
Low doses can cause excitation with possibility of convulsions and high doses can result in unconsciousness, respiratory depression and even death
95
What drug class do organophosphates belong to
Irreversible anticholinesterases
96
how do you treat organophosphate poisoning
the use of atropine I.V., artificial respiration and pralidoxime I.V.. Pralidoxime can reverse an irreversible anticholinesterase if given within a few hours of phosphorylation, otherwise the phosphorylated enzyme ‘ages’ and becomes fully irreversibl
97
What drug is used to treat organophosphate poisoning
Pralidoxime
