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Pharmacology Year 2 > Cholinomimetics > Flashcards

Cholinomimetics Flashcards

1
Q

Recall the synthesis and break down of acetylcholine

A

Acetyl CoA + Choline => ACh + CoA; catalysed by Choline acetyltransferase (CAT)

Acetylcholine => Choline + Acetate; catalysed by Acetylcholinesterase

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2
Q

Why are the receptors described as nicotinic and muscarinic?

A

Muscarinic effects are those that can be replicated by muscarine.
Nicotinic effects are those that can be replicated by nicotine

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3
Q

Name a competitive muscarinic receptor antagonist

A

Atropine

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4
Q

Name a nicotinic receptor antagonist

A

Tubocararine

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5
Q

Briefly state where nicotinic and muscarinic receptors are found in the ANS

A

Nicotinic: found ‘between pre- and post-ganglionic neurones’ in both SNS and PNS pathways; as well as the NMJ

Muscarinic: found on PNS effectors and sweat glands (innervated by SNS)

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6
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

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7
Q

What types of receptor are each of the muscarinic receptors

A

M1, M3, M5 = stimulatory GPCR; IP3 and DAG mediated transduction

M2 and M4 = inhibitory GPCR; decrease cAMP production

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8
Q

Describe the structure of nicotinic receptors

A
  • Ionotropic type 1/ligand-gated ion channel

- 5 subunits (any of α β γ δ ε) which determine ligand binding properties

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9
Q

What combination of subunits are found at the NMJ, and at ganglia

A

Muscle type: 2α β δ ε

Ganglion type: 2α 3β

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10
Q

How do the effects of acetylcholine on nicotinic receptors compare to its effects on muscarinic receptors?

A

Relatively weak on nicotinic compared to muscarinic

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11
Q

What three effects does muscarinic stimulation have on the eye?

A
  1. Ciliary muscle contraction => accommodation for near vision
  2. Sphincter pupillae contraction => constricts pupil (miosis) and improves intraocular fluid drainage
  3. Lacrimation
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12
Q

What is glaucoma?

A

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

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13
Q

Describe the passage of aqueous humour through the eye

A
  • Aqueous humour is produced by capillaries in the ciliary body (via the actions of carbonic anhydrase)
  • Aqueous humour passes into the anterior chamber
  • Contraction of sphincter pupillae (iris circular muscle) opens pathway for aqueous humour, allowing drainage via the trabecular meshwork and canals of Schlemm => reduced intraocular pressure
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14
Q

Describe the muscarinic effects on the heart

A

Binding of ACh to the M2 receptors in the atria and nodes => decreased cAMP production => decreased Ca2+ influx and increased K+ efflux => decreased CO and decreased HR

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15
Q

Describe the muscarinic effects on the vasculature

A
  • ACh binds to M3 receptors on vascular endothelial cells to stimulate NO release which induces vascular smooth muscle relaxation/vasodilation (due to K+ efflux)
  • Note however that most blood vessels do not have parasympathetic innervation (only coronary) but M3 receptors ARE found in many blood vessels
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16
Q

Describe the muscarinic effects on Non-Vascular Smooth Muscle

A

Smooth muscle that does have PNS innervation responds in the opposite way to vascular muscle – i.e. it contracts (because the M3 receptor is Gq)

e.g. bronchoconstriction, increased peristalsis, increased micturition

17
Q

State the muscarinic effects on exocrine glands

A
  • Salivation
  • Increased bronchial secretions
  • Increased gastro-intestinal secretions (including gastric HCl production)
  • Increased sweating (SNS-mediated)
18
Q

What is the difference between directly and indirectly acting cholinomimetic drugs

A

Direct = Muscarinic receptor agonist

Indirect = Anticholinesterase (Increase effect of normal parasympathetic nerve stimulation by increasing duration of acetylcholine activity in the synapse)

19
Q

Name two muscarinic receptor agonists

A

Bethanechol (choline esters)

Pilocarpine (alkaloids)

20
Q

State the characteristics and clinical use of pilocarpine

A
  • Non-selective; good lipid solubility; t1/2 ≈ 3-4h

- Local treatment for glaucoma

21
Q

What are the side effects of pilocarpine

A

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

22
Q

State the characteristics and clinical use of bethanechol

A
  • Produced by adding methyl group to ACh => M3 selective
  • Resistant to degradation, orally active and with limited access to the brain; t1/2 ≈ 3-4h
  • Used to assist bladder emptying and to enhance gastric motility
23
Q

What are the side effects of bethanechol

A

Sweating, impaired vision, bradycardia, hypotension, respiratory difficulty

24
Q

Name three reversible and three irreversible anticholinesterase

A

Physostigmine, neostigmine, donepezil (‘Aricept’)

Ecothiopate, dyflos, sarin (organophosphates)

25
Q

What are the two types of cholinesterase

A

Acetylcholinesterase (true or specific cholinesterase)

Butyrylcholinesterase (pseudocholinesterase)

26
Q

Summarise the main differences between acetylcholinesterase and butyrylcholinesterase

A

Acetylcholinesterase:

  • Found in all cholinergic synapses
  • Very rapid action
  • Highly selective for acetylcholine

Butyrylcholinesterase:

  • Found in plasma and most tissues but not cholinergic synapses
  • Broad substrate specificity (hydrolyses other esters e.g. suxamethonium)
  • Causes low plasma acetylcholine
  • Shows genetic variation
27
Q

Describe the effects of increasing the dosage of cholinesterase inhibitors

A

LOW = enhanced muscarinic activity

MODERATE = Increased transmission at ALL autonomic ganglia (nAChRs) and further enhancement of muscarinic activity

HIGH = Depolarising block at autonomic ganglia & NMJ (toxic)

28
Q

How do reversible anticholinesterase drugs work?

A
  • They compete with acetylcholine for the active site on the cholinesterase enzyme. - They donate a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding
  • Carbamyl group is removed by slow hydrolysis
29
Q

State the characteristics and clinical use of physostigmine

A
  • Tertiary amine that primarily acts at the postganglionic parasympathetic synapse; t1/2 ≈ 30 mins
  • Used to treat glaucoma and atropine poisoning
30
Q

How do irreversible anticholinesterase drugs work?

A
  • They rapidly react with the cholinesterase active site, leaving a large blocking group that is stable and resistant to hydrolysis
  • Recovery may require the production of new enzymes (days/weeks)
31
Q

State the characteristics and clinical use of ecothiopate

A
  • Potent anticholinesterase

- Used as eye drops to treat glaucoma (prolonged action)

32
Q

What are the side effects of ecothiopate?

A

Sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty

33
Q

Which anticholinesterases can cross the blood brain barrier? State the effects of low and high doses

A

Non-polar anticholinesterases (e.g. physostigmine; nerve agents).

LOW = CNS excitation with possibility of convulsions

HIGH = Unconsciousness, respiratory depression, death

34
Q

Describe the treatment of organophosphate poisoning

A

Pralidoxime (iv): ‘unblocks’ cholinesterase enzyme (used within first few hours of poisoning)
Atropine (iv): inhibit muscarinic receptors
Artificial respiration

Pharmacology Year 2 (32 decks)

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