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Y2 LCRS - pharmacology > Cholinomimetics > Flashcards

Cholinomimetics Flashcards

1
Q

Cholinomimetics

A

Mimics action of ACh in the nervous system

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2
Q

Synthesis, release and metabolism of acetylcholine

A

Slide 2 [pic]

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3
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

Slide 6 [pic]

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4
Q

Muscarinic receptors: 3 main subtypes

A

M1: salivary glands, stomach, CNS
M2: Heart
M3: Salivary glands, bronchial/visceral SM, sweat glands, eye

Slide 7 [pic]

NOTE:
All muscarinic receptors are G-protein-coupled receptors
M1, M3 and M5 = binds Gq protein, stimulates IP3 DAG
M2 and M4 = binds Gi protein, reduces cAMP

General rule = response tends to be excitatory (apart from M2 = inhibitory)

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5
Q

Nicotinic receptors

A

Ligand gated ion channels
5 subunits: alpha, beta, gamma, delta, epsilon
Subunit combination determines ligand binding properties of the receptor

Muscle type: 2alpha, beta, delta, epsilon
Ganglion type: 2 alpha, 3 beta (CNS - similar)

Effects of ACh relatively weak

Slide 8 [pic]

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6
Q

Muscarinic cholinergic target systems

A

Slide 9 [pic]

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7
Q

Muscarinic effects of eye

A

Contraction of 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)

Slide 11 [pic]
Aqueous humour provides oxygen and nutrients (it doesn’t have a blood supply)
NOTE: in glaucoma, the iris becomes folded/ruffled - rate of drainage is reduced (intra-ocular pressure rises - can damage retina and/or optic nerve)

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8
Q

Muscarinic effects in heart

A

M2 AChR in atria and nodes
Decrease cAMP
Decreased Ca2+ entry —> decreased cardiac output
Increased K+ efflux —> decreased heart rate
Inotropic effect

Slide 12 [pic]

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9
Q

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

Slide 13 [pic]

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10
Q

Muscarinic effects on 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

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11
Q

Muscarinic effects on non-vascular smooth muscle

A

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

Lung: bronchoconstriction
Gut: increased peristalsis (motility)
Bladder: increased bladder emptying

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12
Q

Muscarinic effects of exocrine glands

A

Salivation
increased bronchial secretions
Increased GI secretions (including gastric HCl production)
Increased sweating (SNS-mediated)

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13
Q

Muscarinic effects: summary

A

Slide 17 [pic]

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14
Q

Two mainn groups of drugs

A

Directly acting cholinomimetic drugs

Indirectly acting cholinomimetic drugs

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15
Q

Directly acting cholinomimetic drugs

A

Typical agonists at muscarinic receptors:
1, choline esters (bethanechol)
2. Alkaloids (pilocarpine)

Slide 18 [pic]

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16
Q

Pilocarpine

A

Non-selective muscarinic agonist; good lipid solubility
T(1/2)=3-4 hours
Particularly useful in ophthalmology as a local treatment for glaucoma (eyedrops)
Side effects: blurred vision, sweating, GI disturbance and pain, hypotension, respiratory distress

17
Q

Bethanechol

A

Minor modification of acetylcholine, produces an M3 AChR selective agonist
Resistant to degradation, orally active and with limited access to the brain
T(1/2) = 3-4 hours
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)

18
Q

Indirectly acting cholinomimetic drugs

A

Increase effect of normal parasympathetic nerve stimulation
Target site = acetylcholinesterase in synaptic cleft
Reversible anticholinesterases = physostigmine, neostigmine, donepezil (‘Aricept’ - treatment for Alzheimer’s)
Irreversible anticholinesterases = ecothiopate, dyflos, sarin

19
Q

Cholinesterase enzymes

A

Metabolise acetylcholine to choline and acetate
Two types which differ in distribution, substrate specificity and function:
- acetylcholinesterase (true or specific cholinesterase)
- butyrylcholinesterase (pseudocholinesterase)

20
Q

Acetylcholinesterase

A

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

Slide 23 [pic]

21
Q

Butyrylcholinesterase

A

Found in all 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

22
Q

Effects of cholinesterase inhibitors

A

Low dose:
- enhanced muscarinic activity
Moderate dose:
- further enhancement of msucarinic activity
- increased transmission at all autonomic ganglia (nAChRs)
High dose (toxic):
- depolarising block at autonomic ganglia and NMJ

23
Q

Reversible anticholinesterase drugs

A

Physostimine, 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

Slide 26 [pic]

24
Q

Physostigmine

A

Primarily acts at the postganglionic parasympathetic synapse
T(1/2) = 30 mins
Used in the treatment of glaucoma, aiding intraocular fluid drainage
Also used to treat atropine/poisoning, particularly in children

25
Q

Irreversible anticholinesterase drugs

A

Organophsophate 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)

Slide 28 [pic]

26
Q

Ecothiopate

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 prolonged duration of action
Systemic side effects: sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty

27
Q

Anticholinesterase drugs and the CNs

A

Non-polar anticholinesterases (e.g. physostigmine; nerve agents) can cross the blood brain barrier
Low doses = excitation with possibility of convulsions
High doses = unconsciousness respiratory depression, deathq

28
Q

Treatment of organophosphate poisoning

A

Accidental exposure to organophosphates used in insecticides, or deliberate use as nerve agents can causes severe toxicity (increased muscarinic activity = CNS excitation = depolarising neuromuscular block)
Treatment = atropine , artificial respiration, pralidoxime

NOTE: phosphorylated enzyme ‘ages’ within few hours

Slide 31 [pic]

29
Q

Summary

A

Slide 32 [pic]

30
Q

Anticholinesterase drugs have the ability to increase activity at which synapses within the autonomic nervous system?

  1. All autonomic synapses
  2. Pre- and post-ganglionic parasympathetic synapses
  3. Pre- and post-ganglionic sympathetic synapses
  4. Post-ganglionic parasmpathetic synpases only
  5. Pre-ganglionic sympathetic synapses only
A

2

31
Q

Anticholinesterase drugs can be used to treat which of the following conditions?

  1. Asthma
  2. Glaucoma
  3. Hypotension
  4. Motion sickness
  5. Peptic ulcer disease
A

2

Y2 LCRS - pharmacology (7 decks)

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