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Y2 LCRS 1 - Pharmacology and Therapeutics > Cholinomimetics > Flashcards

Cholinomimetics Flashcards

1
Q

Describe the synthesis, release and metabolism of acetylcholine.

A

Synthesis

Acetyl coA + choline → Ach + coA

  • Catalysed by choline acetyltransferase (CAT)

Release

  • ACh packaged into vesicles
  • AP triggers Ca2+ influx into pre-synaptic terminal
  • This stimulates vesicle exocytosis and release of ACh into synpatic cleft

Metabolism

  • Acetylcholinesterase, present in the synaptic cleft, breaks down ACh:
    • ACh → choline + acetate
  • Choline and acetate can be recycled back into the pre-synaptic nerve terminal so they can be used to make more ACh
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2
Q

What is the difference between muscarinic and nicotinic effects?

A

Muscarinic effects are those that can be replicated by muscarine (muscarinic receptor agonist)

Nicotinic effects are those that can be replicated by nicotine (nicotinic receptor agonist)

NOTE: ACh acts on both muscarinic and nicotinic receptors

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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

After atropine blockade of muscarinic actions, what can large doses of ACh induce?

A

Large doses of ACh can induce similar effects to those caused by nicotine

  • Because the muscarinic receptors are blocked so therefore you get more ACh binding to the nicotinic receptors
  • These nicotinic receptors also respond to nicotine therefore nicotine and ACh would have similar effects in this case
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5
Q

Which branch of the ANS do muscarinic actions correspond to?

A

Parasympathetic nervous system

  • Muscarinic receptors are present on parasympatheitc effector organs
  • EXCEPTION: sweat glands have muscarinic ACh receptors but have sympathetic stimulation (i.e. post-ganglionic neurone terminated in sympathetic trunk)
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6
Q

State where you would find the different muscarinic receptor subtypes.

A

M1

  • Salivary glands
  • Stomach
  • CNS

M2

  • Heart

M3

  • Salivary glands
  • Bronchial/visceral smooth muscle
  • Sweat glands
  • Eye

M4 - CNS

M5 - CNS

NOTES:

  • M1, M2 and M3 are the main receptor subtypes
  • Muscarinic receptors are generally excitatory (stimulates muscle contraction, secretion) except for on the heart (decreases heart rate and contractlilty)
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7
Q

What type of receptor are all muscarinic receptors?

A

G-protein coupled receptors

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8
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 (odds)

  • They stimulate phospholipase C (PLC) which converts PIP2 increases IP3 and DAG
  • Second messengers: IP3 and DAG - increased

M2 and M4 = Gi protein linked receptors (evens)

  • They inhibit adenyl cyclase which would convert ATP to cAMP
  • Second messenger: cAMP - decreased
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9
Q

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

A

Nicotinic receptors are ligand-gated ion channels (i.e. ion channel opens when ligand binds)

Nicotinic receptors consist of 5 subunits:

  • α = alpha
  • β = beta
  • γ = gamma
  • δ = delta
  • ε = epsilon

The combination of subunits determines its ligand binding properties.

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10
Q

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

A

Two main nACh receptor types:

  • Muscle
  • Autonomic ganglion

Muscle - 2α, β, δ, ε

Ganglion - 2α 3β (similar structure to this for nACh receptors found in the CNS)

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11
Q

What is the relevance of having two nicotinic receptor subtypes in terms of pharmacology?

A
  • This difference in subunit combination gives slightly different ligand-binding properties
  • This means that drugs can be developed which are more selective for one receptor subtype than the other (e.g. drugs which act on the NMJ)

REMEMBER: The drugs are never 100% selective so they also have the potential to affect the other (unwanted) receptor subtype

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12
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

  • Relatively weak - i.e. you need more ACh to stimulate nicotinic receptors
    • This is probably because ACh has a lower affinity for nicotinic receptors so you need more collisions between receptor ligand in order for proper binding to take place
    • Reduced chance of proper binding per collision
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13
Q

What three effects does muscarinic stimulation have on the eye?

A

Contraction of the ciliary muscle

  • Accommodates for near vision
  • It does this by making the lens thicker so there is more refraction of light from nearby objects onto the retina

Contraction of sphincter pupillae (circular muscle of the iris)

  • This constricts the pupil (miosis) and increases drainage of intraocular fluid

Lacrimation (tears)

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14
Q

What is glaucoma?

A

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

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15
Q

How can a muscarinic agonist be used to treat glaucoma?

A
  • In angle-closure glaucoma, the angle between the iris and cornea is too small (closed)
  • This which blocks the flow of the aqueous humour out of the iris
  • Contraction of sphincter pupillae (cicular muscle of iris) opens up this angle
  • This provides a pathway for aqueous humour drainage via the canals of Schlemm → reduced intraocular pressure

REMEMBER: This is only relevant for angle-closure glaucoma (there are other types of glaucoma which have a different cause for the raised intraocular pressure)

NOTE: Aqueous humour drains through the trabecular meshwork into the canals of Schlemm

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16
Q

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

A
  • Decrease in intracellular Ca2+ in heart muscle decreases myocardial contractility
    • ↓ contractility → ↓ force of contraction → ↓ CO
    • This is because Ca2+ is required to bind to the muscle fibre to stimulate it to contract
    • Less Ca2+ binding means less actin-myosin cross bridges and hence reduced force of contraction
  • Increasing K+ efflux from the conductive tissue in the heart decreases heart rate
    • This is because it hyperpolarises (more -ve) the cells meaning that it takes longer to reach the threshold potential for generating an AP
    • Reduced AP frequency = reduced HR

NOTE: receptors present in atria (i.e. atrial muscle) and nodes (i.e. SAN and AVN)

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17
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 ACh receptor
  • NO induces vascular smooth muscle relaxation → vasodilation
  • Result is a decrease in TPR

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

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18
Q

Summarise the muscarinic effects on the cardiovascular system.

A
  • Decreased heart rate (bradycardia)
  • Decreased cardiac output
    • Due to decreased atrial contraction
    • Reduced atrial contraction → reduced blood volume emptied from atria into ventricles → reduced blood volume ejected from ventricles - SV
  • Vasodilaation and reduced TPR
    • Due to stimulation of NO production

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

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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 → diffuculty breathing
  • GI tract – increased peristalsis (motility) → GI pain
  • Bladder – increased bladder emptying
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20
Q

Describe the muscarinic effects on exocrine glands.

A

Increases secretions from exocrine glands

  • Increased salivation
  • Increased lacrimation (tears)
  • Increased bronchial secretions (e.g. mucus) → diffuculty breathing
  • Increased GI secretions (including gastric HCl production) Increased sweating (SNS-mediated)
21
Q

What are the two types of cholinomimetic drug?

A

Directly Acting – muscarinic receptor agonists

Indirectly Acting – acetylcholinesterase inhibitors (anticholinesterases)

22
Q

State two types of muscarinic receptor agonists 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

  • It stimulates ALL muscarinic receptor subtypes
24
Q

What is the half-life of pilocarpine?

A

Approximately 3-4 hours

  • Relatively long half life
  • This is due to its good lipid solubility
    • This makes it harder to be cleared from the plasma (undergo renal excretion)
    • Its lipid solubililty means that it is reabsorbed back into the blood from the urine via the kidney tubular cells (lipid membranes)
25
Q

What is pilocarpine used to treat?

A

Particularly useful in ophthalmology as a local treatment for glaucoma

  • Local (in this case) = eyedrops
26
Q

State some side effects of pilocarpine.

A
  • Blurred vision
    • PNS allows for near vision (accommodation)
    • This means that distant things look blurry
  • Hypotension
  • Sweating
  • Respiratory difficulty
  • GI disturbance and pain
    • Due to excessive motility and over-exertion
27
Q

Describe the selectivity of bethanechol.

A

M3 selective agonist

NOTE:

  • Bethanechol has a very similar structure to ACh
  • Only a minor modification to ACh which is non-selective creates an agonist which is selective (i.e. more selective to M3 than the others but can still act on the others)
28
Q

What is the half-life of bethanechol?

A

Approximately 3-4 hours

  • Resistant to degradation
    • This is probably what gives it a longer half-life
    • Not broken down by ACh so can diffuse back into plasma once its had its effect (takes longer to be cleared from plasma)
  • Orally active (i.e. taken orally)
  • Limited access to the brain (as not lipid soluble)
29
Q

What is bethanechol mainly used to treat?

A
  • Assist bladder emptying
  • Enhance gastric motility
30
Q

State some side-effects of bethanechol.

A
  • Sweating
  • Impaired (blurred) vision
  • Bradycardia
  • Hypotension
  • Respiratory difficulty
31
Q

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

A

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

NOTE: Cholinesterase metabolises ACh into choline and acetate

32
Q

What are the two types of cholinesterase?

A
  • Acetylcholinesterase
    • True or specific cholinesterase - specific to ACh
  • Butyrylcholinesterase
    • Pseudocholinesterase
    • Not specific to ACh therefore ‘pseudo’

They differ in distribution, substrate specificity and function

NOTE: Technically both are true cholinesterases as they both metabolise choline esters but just different types

33
Q

Describe the properties of acetylcholinesterase.

A
  • Found in all cholinergic synapses
    • Peripheral AND central
  • Very rapid action
    • >10 000 reactions per second
  • Highly selective for acetylcholine
  • Works by hydrolysis reactions
    • It has a serine on its active site with an -OH group
      • R group = CH2OH
    • ​This OH group is required to initate the hydrolysis of the ester bond
34
Q

Describe the properties of butyrylcholinesterase.

A
  • Found in plasma and most tissues but NOT cholinergic synapses
  • Broad substrate specificity
    • Hydrolyses other esters (e.g. suxamethonium)
  • Is principal reason for low plasma acetylcholine
  • Shows genetic variation
35
Q

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

A

Low dose:

  • Enhanced muscarinic activity

Moderate dose:

  • Further enhancement of muscarinic activity
  • Increased transmission at ALL autonomic ganglia
    • because nicotinic ACh receptors are present at all autonomic ganglia

High dose (toxic):

  • Depolarising block at autonomic ganglia & NMJ
    • The nicotinic receptors get over-stimulated, so they shut down
36
Q

Describe the mechanism of action of reversible anticholinesterases.

A

EXAMPLES: Physostigmine, neostigmine

Mechanism of action:

  • Competes with acetylcholine for active site on the cholinesterase enzyme
  • Donates a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding
  • Carbamyl group removed by slow hydrolysis (minutes rather than milliseconds)
    • Spontaneous hydrolysis - just slow
  • Increase duration acetylcholine remains in synapse
    • As ACh cannot be broken down until the carbamyl group is removed which takes time
37
Q

Describe the structure of physostigmine.

A

It is a naturally occurring tertiary amine.

38
Q

Where does physostigmine primarily act?

A

At the postganglionic parasympathetic synapse

39
Q

What is the half-life of physostigmine?

A

30 mins

40
Q

What is physostigmine used to treat?

A

Glaucoma

  • Aids in introcular fluid drainage

Atropine poisoning

  • Atropine is a competitive muscarinic antagonist meaning that it is surmountable (i.e. effect can be overcome)
  • Physostigmine increases the concentration of acetylcholine at the synapse so that the acetylcholine can outcompete the atropine
41
Q

What type of compound are irreversible anticholinesterases?

A

Organophosphates, e.g:

  • Ecothiopate
  • Dyflos
  • Parathion
  • Sarin
42
Q

Describe the mechanism of action of irreversible anticholinesterases. Describe some properties of ecothiopate.

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 (takes days or weeks)

Ecothiopate:

  • Potent inhibitor of acetylcholinesterase
  • Slow reactivation of the enzyme by hydrolysis takes several days
    • ​Essentially it can be removed from the enzyme by hydrolysis so this takes a very long time
    • Therefore it is more efficient to just make new enzymes
    • Based on this it is considered to be an irreversible inhibitor
43
Q

Which is the only organophosphate which is in clinical use? What are the others used for?

A

Ecothipate in clinical use

Others commonly used as:

  • Insecticides
    • Affects NS of insects
    • And becuase they are much smaller the dose is much more toxic to them than larger animals such as humans
  • Nerve gas (agent) = organic chemicals which disrupt neural transmission mechanisms, specifically at synapses by irreversibly blocking acetylcholinesterase
44
Q

What is ecothipate used to treat?

A

Glaucoma

  • Used as eye drops
  • Acts to increase intraocular fluid drainage
  • Prolonged duration of action
45
Q

State some side effects of ecothiopate.

A

Systemic side effects:

  • Blurred vision
  • Sweating
  • Respiratory difficulty
  • Hypotension
  • GI disturbance and pain
  • Bradycardia
46
Q

What type of anticholinesterases can cross the blood-brain barrier and give some examples?

A

Non-polar

  • Physostigmine
  • Nerve agents (organophosphates)
47
Q

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

A

Low doses:

  • CNS excitation with the possibility of convulsions

High doses:

  • Unconsciousness
  • Respiratory depression
  • Death
48
Q

Describe what happens in organophosphate poisoning.

A

Accidental exposure to organophosphates used in insecticides, or deliberate use as nerve agents can cause severe toxicity resulting in:

  • Increased muscarinic activity
  • CNS excitation
  • Depolarising NM block
49
Q

Describe the treatment of organophosphate poisoning.

A

IV atropine:

  • This is a competitive muscarinic receptor agonist so blocks the muscarinic receptors
  • Therefore it reduces the effect of the raised synaptic acetylcholine concentration
  • Patient is put on artifical respiration because of the respiratory depression
    • Caused by the excess acetylcholine at the synapse → depolarising block

If found within the first few hours, the patient should be given IV pralidoxime

  • This can unblock the enzyme
  • BUT phosphorylated enzyme ages within a few hours
    • i.e. Essentially the whole ezyme-organophosphate compound undergoes a conformational change (ageing) meaning that the enzyme is irreversibly resistant to being unblocked by pralidoxime

Y2 LCRS 1 - Pharmacology and Therapeutics (38 decks)

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