Cholinomimetics Flashcards

1
Q

What are cholinomimetics

A

Drugs that mimic the actions of Ach in the nervous system.

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2
Q

Where is the enzyme choline acetyltransferase (CAT) exclusively found

A

In cholinergic nerve terminals.

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3
Q

Outline the synthesis of Ach

A

Ach is synthesised within the nerve terminal from choline, which is taken into the nerve terminal via a specific transporter (choline carrier)- this transporter is not important in terminating the action of Ach
Free choline within the nerve terminal is acetylated by a cytosolic enzyme, choline acetyltransferase (CAT), which transfers the acetyl group from acetyl coA to choline- forming acetylcholine.
The rate-limiting process in ACh synthesis appears to be choline transport, which is determined by the extracellular choline concentration and hence is linked to the rate at which Ach is being released.

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4
Q

Describe the action of cholinesterase

A

Present in the pre-synaptic nerve terminals, and ACh is continually being hydrolysed and resynthesized. Inhibition of the nerve terminal cholinesterase causes the accumulation of surplus ACh in the cytosol, which is not available for release by nerve impulses (although it is able to leak out via the choline carrier).
Most of the ACh synthesised, however, is packaged into synaptic vesicles, in which its concentration is extraordinarily high (about 100mmol/L), and from which its release occurs by exocytosis triggered by Ca2+ entry into the nerve terminal.

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5
Q

Describe the packaging of ACh into vesicles

A

Cholinergic vesicles accumulate ACh actively, by means of a specific transporter belonging to a family of amine transporters (ACh carrier).
Accumulation of ACh is coupled to the large electrochemical gradient for protons that exists between acidic intracellular organelles and the cytosol; it is blocked selectively by the experimental drug vesamicol.

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6
Q

Describe the release of ACh from the vesicles

A

Following its release, ACh diffuses across the synaptic cleft to combine with receptors on the postsynaptic cells.
Some of it succumbs on the way to hydrolysis by acetylcholinesterase, an enzyme that is bound to the basement membrane that lies between the pre- and postsynaptic membranes.
At fast cholinergic synapses (e.g the neuromuscular and ganglionic synapses), but not at slow ones (smooth muscle cells, glands, heart), the released ACh is hydrolysed very quickly so that it acts very rapidly.

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7
Q

What are the pharmacological actions of ACh distinguished by

A

Two types of activity:
muscarinic- mimicking the effects of muscarine (the active principle of the poisonous mushroom Amanita muscaria)
Nicotinic- mimicking the effects of nicotine.

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8
Q

Where do muscarine and nicotine originate from

A

Comes from amanita muscaria and nicotiana tabacum

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9
Q

Summarise muscarinic vs nicotinic effects

A

Muscarinic effects are those that can be replicated by muscarine, and can be abolished by low doses of the antagonist atropine

Muscarinic actions correspond to those of parasympathetic stimulation

After atropine blockade of muscarinic actions larger doses of acetylcholine can induce effects similar to those caused by nicotine

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10
Q

Compare some nicotinic and some muscarinic actions

A

Muscarinic effects- fall in BP (arteriolar vasodilation) and slowing of the heart
Nicotinic effects- initial rise in BP (stimulation of sympathetic ganglia and consequent vasoconstriction), and a secondary rise resulting from the release of adrenaline.

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11
Q

What do the muscarinic actions correspond to

A

The ACh released at postganglionic parasympathetic nerve endings, with two significant exceptions:

  1. ACh causes generalised vasodilation, even though most blood vessels have no parasympathetic innervation. This is an indirect effect: ACh (like many other mediators) acts on endothelial cells to release nitric oxide, which relaxes smooth muscle. The physiological function of this is uncertain. because ACh is not normally present in circulating blood.
  2. ACh evokes secretion from sweat glands, which are innervated by cholinergic fibres of the sympathetic nervous system.
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12
Q

What do the nicotinic actions correspond to

A

To those of ACh acting on autonomic ganglia of the sympathetic and parasympathetic systems, the motor endplate of voluntary muscle and the secretory cells of the adrenal medulla.

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13
Q

Summarise the muscarinic receptors

A

Muscarinic receptors (mAChRs) are typical G-protein coupled receptors, and five molecular subtypes (M1-M5) are known.

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14
Q

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

A
M1:	Salivary glands
		Stomach
		CNS
M2:	Heart
M3:	Salivary glands
		Bronchial/visceral SM
		Sweat glands
		Eye
M4:	CNS
M5:	CNS
NOTE: muscarinic receptors are generally excitatory except for on the heart
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15
Q

Summarise the intracellular effects of the different muscarinic receptors

A

The odd-numbered members of the group (M1,M3,M5) couple with Gq to activate the inositol phosphate pathway
The even-numbered receptors (M2,M4) act through Gi to open potassium (Kir) channels causing membrane hyperpolarisation; they also inhibit adenylyl cyclase but intracellular cAMP is usually low.
Muscarinic agonists with either transduction mechanism also activate the mitogen-activated protein kinase pathway.

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16
Q

Describe the M1 receptors

A

Found mainly on CNS, peripheral neurons, gastric parietal cells and lacrimal and salivary glands
They mediate excitatory effects, for example, the slow muscarinic excitation (slow epsp) mediated by ACh in sympathetic ganglia and central neurons
This excitation is produced by a decrease in K+ conductance, which causes membrane depolarisation.
Deficiency of this kind of ACh-mediated effect in the brain is possibly associated with dementia, although transgenic M1-receptor knockout mice show only slight cognitive impairment.
M1 receptors are also involved in the increase of gastric acid secretion following vagal stimulation.

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17
Q

Describe the M3 receptors

A

Found in glandular and smooth muscle
produce mainly excitatory effects i.e stimulation of glandular secretions (salivary, bronchial, sweat etc) and contraction of visceral smooth muscle.
M3 receptor activation also causes relaxation of some smooth muscles (mainly vascular) via the release of nitric oxide from neighbouring endothelial cells.
M3 receptors also occur in specific locations in the CNS.

G.I smooth muscle contraction, ocular accommodation too
Rise in IP3 and Ca2+

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18
Q

Summarise the M4 and M5 receptors

A

Largely confined to the CNS, and their functional role is not well understood, although mice lacking these receptors do show behavioural changes.
No therapeutic uses currently.
M4 may be involved in enhanced locomotion

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19
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

20
Q

Essentially, what type of receptors are muscarinic receptors

A

GPCRs- their activation causing:
activation of PLC (hence formation of IP3 and DAG as secondary messengers)
inhibition of adenylyl cyclase- hence reducing the formation of cAMP.
activation of potassium channels and/or inhibition of calcium channels

21
Q

Summarise potential new therapeutic roles for mAChR ligands

A

Cytokine secretion from lymphocytes and other cells is regulated by M1 and M3 receptors, while M2 and M4 receptors affect cell proliferation in various situations.

22
Q

What happens in response to nicotinic receptor activation

A

Na+ influx- but also some K+ efflux.

23
Q

Summarise the nicotinic receptors

A

Muscle receptors are confined to the skeletal NMJ; ganglionic receptors are responsible for fast transmission at sympathetic and parasympathetic ganglia; and CNS-type receptors are heterogenous with respect to their molecular composition and location.

24
Q

Where are many of the CNS nicotinic receptors found

A

presynaptically and serve to facilitate or inhibit the release of other mediators, such as glutamate or dopamine.

25
Q

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

A

Nicotinic receptors consist of 5 subunits (alpha, beta, gamma, delta or epsilon)
The combination of subunits determines its ligand binding properties
Pentameric structures
The five subunits each possess four membrane-spanning helical domains and one of these helices from each subunit forms the central pore.

26
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 CNS also 2 alpha + 3 beta- but different types of each one

27
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

28
Q

List the muscarinic cholinergic target systems

A
Eye
Salivary glands
Lungs
Heart
Vasculature
Sweat Glands
Gut
Bladder
29
Q

Summarise the end result of muscarinic effects

A

combined vasodilation, decreased HR and decreased CO = sharp BP drop

30
Q

Describe the muscarinic effects on the heart

A

M2 AChR in
atria and nodes
Stimulation of these receptors- decreased cAMP
This results in:
Decreased Ca2+ entry and increased K+ efflux
Decreasing Q and HR respectively.

Negative inotropic and chronotropic effects

31
Q

What is important to remember about blood vessels

A

Most blood vessels don’t have PSNS innervation.

However, they do express muscarinic receptors and so can be exploited by exogenous drugs

32
Q

Describe the muscarinic effects on the vasculature

A

Most blood vessels do not have parasympathetic innervation

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

NO induces vascular smooth muscle relaxation

Result is a decrease in TPR

33
Q

When are the muscarinic effects on the vasculature more relevant

A

This is more relevant to the clinical use of cholinomimetics than normal physiology

34
Q

Summarise the muscarinic effects on the cardiovascular system

A

Decreased heart rate (bradycardia)

Decreased cardiac output (due to decreased atrial contraction)

Vasodilatation (stimulation of NO production)

All of these combined can lead to a sharp drop in blood pressure

35
Q

How do the muscarinic effects on non-vascular smooth muscle compare to that of vascular smooth muscle

A

Smooth muscle that does have parasympathetic innervation responds in the opposite way to vascular muscle – i.e. it contracts

36
Q

Summarise the muscarinic effects on non-vascular smooth muscle

A

Lung: Bronchoconstriction

Gut: Increased peristalsis (motility)

Bladder: Increased bladder emptying

37
Q

What is colicky G.I pain due to

A

Contraction of the smooth muscle in the gut

38
Q

Summarise the muscarinic effects on the exocrine glands

A

Salivation

Increased bronchial secretions

Increased gastro-intestinal secretions (including gastric HCl production)

Increased sweating (SNS-mediated)

39
Q

Summarise the muscarinic effects on the eye

A

Contraction of the ciliary muscle: accommodation for near vision

Contraction of the sphincter pupillae (circular muscle of the iris): Constricts pupil (miosis) and improves drainage of intraocular fluid

Lacrimation (tears)

40
Q

What is the effect of contraction of the sphincter pupillae muscle on the drainage of intra-ocular fluid

A

Contraction of sphincter pupillae opens pathway for aqueous humour, allowing drainage via the canals of Schlemm and reducing intra-ocular pressure

41
Q

Describe the contraction of the ciliary muscle

A

Allows the lens to bulge
Becomes more convex
Allowing us to accommodate for near vision- need a more powerful lens- as light rays are heading outwards- so we need two bring light rays back onto the retina quickly

42
Q

How does the lens need to be when looking at distant objects

A

Flat- to collect all the light rays

43
Q

Where is the aqueous humour produced

A

Ciliary body- epithelial cells cover it
Aquous humour flows forward into the anterior chambers of the eye
Bathes the lens and cornea- don’t have blood supply- so this supplies oxygen and nutrients to these regions
Drains into the margin of the eye- Canal of schlemm
Drains through these into the venous system
Continuous flow of aqueous humour.

44
Q

Describe closed angle glaucoma

A

Angle of drainage into canal of schlemm changes- becoming more occluded
This results in a lower rate of drainage- raining the intraocular pressure- damaging the retina or optic nerve which can lead to blindness.

45
Q

Summarise the effects of muscarinic receptor activation

A

Decreased heart rate

Decreased blood pressure

Increased sweating

Difficulty breathing

Bladder contraction

Gastrointestinal pain

Increased salivation and tears