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Year 2 PHARM- mine > Cholinomimetics > Flashcards

Cholinomimetics Flashcards

1
Q

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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2
Q

which neurons are cholinergic?

A

motor neurons

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3
Q

what receptors are in all autonomic ganglia?

A

nicotinic

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4
Q

where are muscarinic receptors found?

A

PNS on effector organ

SNS on effector organ on sweat glands

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5
Q

what are the 3 main muscarinic receptors subtypes

A

M1
M2
M3

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6
Q

M1 receptor examples

A

M1: Salivary glands
Stomach
CNS

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7
Q

M2 receptor examples

A

M2: Heart

decreases heart rate

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8
Q

M3 receptor examples

A

M3: Salivary glands
bronchial/visceral SM
Sweat glands
Eye

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9
Q

Which receptors are Gq and which ones are Gi

A

M1, M3 & M5 Gq: stimulates PLC (phospholipase C) to increase production of IP3 and DAG

M2 & M4 Gi reduces the production of cAMP

odds= Gq
Evens =Gi

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10
Q

where are M4 and M5

A

in the CNS

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11
Q

Muscarinic receptors are generally excitatory, exception?

A

M2 on the heart are inhibitory

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12
Q

what are all muscarinic receptors

A

type 2 receptors- G protein coupled

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13
Q

what type of receptors are nicotinic receptors

A

ligand gated ion channels

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14
Q

what subunits make up the nicotinic receptors

A

5 subunits: α β γ δ ε

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15
Q

subunit combination determines?

A

the ligand binding properties of the receptor

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16
Q

what do muscle types have?

A

Muscle type: 2α β δ ε

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17
Q

what do ganglion types have?

A

Ganglion type: 2α 3β (CNS - similar)

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18
Q

which receptor is acetylcholine weaker in?

A

Effects of ACh weaker in nicotinic compared to muscarinic

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19
Q

what are the three main 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)

20
Q

what is glaucoma?

A

increase in intraocular pressure- this can cause damage to the optic nerves and retina and lead to blindness

21
Q

what is aqueous humour and what is it used for?

A 
Aqueous humour is generated by the capillaries of the 
ciliary body
•
The aqueous humour is generated and it flows into the anterior chamber of the 
eye 
•
Its role is to supply oxygen and nutrients to the 
lens
and 
cornea
because they 
don’t have a blood supply 
•
The aqueous humour diffuses forwards across the lens, then across the cornea 
and it drains through the 
canals of Schlemm
back into the venous system
22
Q

what happens in angle-closure glaucoma?

A

the angle between cornea and the iris becomes narrowed

this narrowing reduces the drainage of intraocular fluid via the canals of schlemm

23
Q

what happens when you give a patient with angle-closure glaucoma a muscarinic agonist?

A

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

24
Q

what are the muscarinic effects on the heart?

A

M2 receptors are inhibitory, and found in atria and both nodes

  • decreases cAMP
  • decreased calcium entry = decreased cardiac output
  • increased potassium efflux = decreased heart rate
25
Q

muscarinic effects on the vasculature

-what happens when acetylcholine acts on vascular endothelial cells?

A

Most blood vessels do not have parasympathetic innervation- BUT they do have receptors

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

NO induces vascular smooth muscle relaxation- leading to vasodilation

Result is a decrease in TPR

26
Q

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

27
Q

Muscarinic effects on non-vascular smooth muscle

A

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

Lung: Bronchoconstriction

Gut: Increased peristalsis (motility)

Bladder: Increased bladder emptying

28
Q

muscarinic effects on exocrine glands

A

Salivation

Increased bronchial secretions

Increased gastro-intestinal secretions (including gastric HCl production)

Increased sweating (SNS-mediated)

29
Q

what are the two types of cholinomimetic drugs

A

directly acting and indirectly acting

30
Q

what are directly acting cholinomimetic drugs?

A

muscarinic receptor agonists

31
Q

what are the two types of muscarinic receptor agonist?

A

Typical agonists at muscarinic receptors

1) choline esters (bethanechol
(2) alkaloids (pilocarpine)

32
Q

Muscarinic Agonists Pilocarpine

-derived from
-selective or non?
-useful to treat?
side effects

A

Muscarinic Agonists: Pilocarpine

Derived from the leaves of a South American shrub Pilocarpus

Non-selective muscarinic agonist; good lipid solubility; t1/2 ≈ 3-4h

Particularly useful in ophthalmology as a local treatment for glaucoma

Side effects: Blurred vision, sweating, gastro-intestinal disturbance and pain, hypotension, respiratory distress

33
Q

Muscarinic Agonists: Bethanechol

  • structure
  • what receptor
  • resistant to?
  • used for
  • side effects
A

Minor modification of acetylcholine, produces an M3 AChR selective agonist

Resistant to degradation by acetylcholinesterase, orally active and with limited access to the brain (t1/2 ≈ 3-4h)

Mainly used to assist bladder emptying and to enhance gastric motility

Side effects: sweating, impaired vision, bradycardia, hypotension, respiratory difficulty

[Cevimeline – newer M3-selective cholinomimetic]

34
Q

indirectly acting cholinomimetic drugs

A

-inhibit acetylcholinesterase
-by doing so they they increase the effect of normal parasympathetic nerve stimulation
Reversible anticholinesterases: physostigmine, neostigmine, donepezil (‘Aricept’)
Irreversible anticholinesterases: ecothiopate, dyflos, sarin

35
Q

what do cholinesterase enzymes do?

A

Metabolise acetylcholine to choline and acetate

36
Q

what are the two types of cholinesterase enzymes and how do they differ?

A

Two types which differ in distribution, substrate specificity and function:

Acetylcholinesterase (true or specific cholinesterase)

Butyrylcholinesterase (pseudocholinesterase)

37
Q

-where are acetylcholinesterase found?
-how fast is the action
highly selective for?

A

Found in all cholinergic synapses (peripheral and central)
Very rapid action (hydrolysis; >10 000 reactions per second)
Highly selective for acetylcholine

38
Q
  • where are butyrylcholinesterase found?

- substrate specificity?

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

39
Q

what are the effects of cholinesterase inhibitors at:

  • low
  • moderate
  • high dose
A

Low dose
Enhanced muscarinic activity (see above)

Moderate dose
Further enhancement of muscarinic activity
Increased transmission at ALL autonomic ganglia (nAChRs)

High dose (toxic)
Depolarising block at autonomic ganglia & NMJ (see PT9 NMJ lecture)
40
Q

what are reversible anticholinesterase drugs and what do they do?

A

Physostigmine, neostigmine

Compete with acetylcholine for active site on the cholinesterase enzyme

Donate a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding

	Carbamyl group removed by 	slow hydrolysis (mins rather 	than msecs)

	Increase duration of acetylcholine 	activity in the synapse
41
Q

Physostigmine

  • occurs?
  • where does it act?
  • used in the treatment of?
A

Naturally occurring tertiary amine from Calabar beans

Primarily acts at the postganglionic parasympathetic synapse (t1/2 ≈ 30 mins)

Used in the treatment of glaucoma, aiding intraocular fluid drainage

Also used to treat atropine poisoning, particularly in children

42
Q

Irreversible Anticholinesterase Drugs

  • what type of compounds are they?
  • what do they react with?
A

Irreversible Anticholinesterase Drugs
are organophosphate compounds.
Organophosphate compounds:
ecothiopate, dyflos, parathion and sarin

Rapidly react with the enzyme
active site, leaving a large blocking
group

This is stable and resistant to hydrolysis - recovery may require the production of new enzymes (days/weeks)

	Only ecothiopate in clinical use, 	but the others are commonly used 	as insecticides (and as nerve gas!)
43
Q
  • what is ecothiopate
  • used for
  • systemic side effects
A

Potent inhibitor of acetylcholinesterase

Slow reactivation of the enzyme by hydrolysis takes several days

Used as eye drops in treatment of glaucoma, acting to increase intraocular fluid drainage with a prolonged duration of action

Systemic side effects: sweating,
blurred vision, GI pain, bradycardia,
hypotension, respiratory difficulty

44
Q

what can anticholinesterase do?

A

Non-polar anticholinesterases (e.g. physostigmine; nerve agents) can cross the blood brain barrier

45
Q

what can low and high doses of anticholinesterase do?

A

Low doses: Excitation with possibility of convulsions

High doses: Unconsciousness, respiratory depression, death

46
Q

treatment of organophosphate poisoning?

A

Accidental exposure to organophosphates used in insecticides, or deliberate use as nerve agents can cause severe toxicity ( muscarinic activity; CNS excitation; depolarising NM block)

Treatment: atropine (iv); artificial respiration; pralidoxime (iv)
NB: Phosphorylated enzyme ‘ages’ within few hours

Year 2 PHARM- mine (17 decks)

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