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Spring 2020: P1 Therapeutics > The Cholinergic System > Flashcards

The Cholinergic System Flashcards

1
Q

List 3 ways in which you can enhance or mimic acetylcholine.

A
  1. Nicotinic receptor agonist
  2. Muscarinic receptor agonist
  3. Acetylcholinesterase inhibition
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2
Q

List 5 ways in which you can block or inhibit acetycholine.

A
  1. Nicotinic receptor antagonist
  2. Muscarinic receptor antagonist
  3. Inhibit choline uptake (hemicholinium)
  4. Inhibit vesicular storage (vesamicol)
  5. Inhibit acetylcholine relase (botulinum toxin)
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3
Q

What receptors exist at the target organ in the parasympathetic nervous system?

A

Muscarinic receptors

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4
Q

What receptors exist at the ganglia and skeletal muscle in the parasympathetic nervous system?

A

Nicotinic receptors

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5
Q

How does acetylcholine form?

A

Cholineacetyltransferase combines choline and acetyl CoA

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6
Q

Describe what happens in the parasympathetic nervous system once acetylcholine is formed.

A
  1. Acetylcholine is packaged into vesicles inside the presynaptic side of the neuron
  2. Once in the vesicle, impulse travels down a neuron and calcium flows in from the outside
  3. Vesicles fuse with exterior membrane and open to release acetylcholine into the synaptic space
  4. Acetylcholine acts on muscarinic receptors, target organs, or nicotinic receptors in the ganglia/skeletal muscle
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7
Q

What does acetylcholinesterase produce?

A

Choline and acetate

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8
Q

What can acetylcholinesterase-produced choline be used for?

A

Recycled for another biosynthesis event

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9
Q

What receptor type exists on the presynaptic terminal in the parasympathetic nervous system?

A

Muscarinic receptors (typical for GPCRs)

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10
Q

What role do muscarinic receptors on the presynaptic terminal play in the parasympathetic nervous system?

A

Serves as a feedback receptor (autoreceptor) to sense how much acetylcholine is in the synapse; if there is excess, it signals to shut off further release

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11
Q

How do M1, M3, and M5 signal?

A

Via intracellular Ca+ increase and PKC activity

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12
Q

Where are M1 receptors found?

A
  • CNS
  • Sympathetic postganglionic cells
  • Presynaptic sites
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13
Q

Where are M3 receptors found?

A
  • Smooth muscle
  • Lungs
  • Eyes
  • Effector cell membranes
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14
Q

How do M2 and M4 signal?

A

Via cAMP decrease and reduced cAMP-dependent PK activity

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15
Q

Where are M2 receptors found?

A
  • Myocardium
  • Smooth muscle
  • Presynaptic sites
  • (K+ channel-linked = slow heart rate)
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16
Q

Where are M4 receptors found?

A

Central nervous system

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17
Q

What type of site does acetylcholine usually bind to?

A

Orthosteric sites

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18
Q

What type of site do muscarinic antagonists usally bind to?

A

Orthosteric sites; competes with acetylcholine (simple, competitive, and reversible)

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19
Q

What analogy can be used when describing binding to allosteric sites?

A

Dimmer switch; doesn’t shut down activity completely

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20
Q

List the 7 clinical uses of anticholinergics.

A
  • Ocular exams
  • Incontinence
  • Irritable bowel syndrome
  • Pre-operative anti-secretory
  • COPD
  • Motion sickness
  • Parkinson’s
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21
Q

How are anticholinergics used to stimulate mydriasis (pupil dilation)?

A

Inhibit acetylcholine action on M3 in the pupillary constrictor muscle

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22
Q

How are anticholinergics used to induce cycloplegia (loss of function/regulation of lens thickness)?

A

Inhibit acetylcholine action on M3 in ciliary muscle

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23
Q

How are anticholinergics used to relax the bladder in order to treat incontinence?

A
  • Via M3 antagonist, which mediates bladder contraction
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24
Q

What receptor indirectly inhibits bladder relaxation?

A

M2

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25
Q

How are anticholinergics used to treat irritable bowel syndrome?

A
  • Anti-spasmodic agents: induce GI tract intestinal paralysis
  • Reduce secretions (useful for ulcers)
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26
Q

How are anticholinergics used in pre-operative anti-secretory settings?

A

Used with inhalant anesthetics to reduce secretion accumulation

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27
Q

How are anticholinergics used to treat COPD?

A
  • Reduce secretions
  • Cause bronchial dilation (used in combination with β-adrenergic agonists)
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28
Q

How are anticholinergics used to treat Parkinson’s disease?

A

As an adjunct to L-DOPA

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29
Q

What do phenyltropanes consist of?

A

Phenyl ring + alkyl chain + tropane

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30
Q

Atropine

A
  • Prototype phenyltropane
  • Natural anticholinergic
  • Antimuscarinic agent
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31
Q

What structural characteristics of anticholinergics helps them travel well and cross the membrane easier?

A
  • Uncharged = lipophilic = crosses easier
  • Tertiary amines: uncharged and travel well
32
Q

Are charged molecules usually used locally or systemically?

A

Locally; charged molecules cannot travel

33
Q

Describe the general mechansim of antimuscarinics.

A

Competitive and irreversible inhibition of muscarinic receptor activation by preventing acetylcholine binding

34
Q

What two general structural classes do most antimuscarinics typically fall into?

A
  • Tertiary amines (used in ocular and CNS)
  • Quaternary amines (used in GI tract and peripheral applications)
35
Q

Describe the selectivity of antimuscarinic, long-lasting tertiary amines.

A

M1/M2/M3 non-selective

36
Q

What are antimuscarinic, long-lasting tertiary amines used to treat?

A

GI/urinary conditions, motion sickness (scopolamine), adjunct for Parkinson’s

37
Q

Describe scopolamine’s relationship to the central nervous system.

A
  • Scopolamine has higher CNS penetration
  • Low doses = drowsiness
  • High doses = hallucinations
38
Q

What antimuscarinic, long-lasting tertiary amine is naturally occurring?

A

Jimsonweed: historically used as a hallucinogen; side effects include confusion, dilated pupils, and tachycardia

39
Q

List two examples of antimuscarinic, long-lasting tertiary amines.

A

Atropine and scopolamine

40
Q

List two examples of antimuscarinic, short-acting tertiary amines.

A

Homatropine and tropicamide

41
Q

How are antimuscarinic, short-acting tertiary amines used?

A

In optical applications due to short duration of action (mydriasis and cycloplegia)

42
Q

Compare homatropine and tropicamide.

A

Homatropine is less toxic, but tropicamide has a shorter duration of action

43
Q

Explain the sedative activity of benztropine.

A
  • Tertiary amine used to treat Parkinson’s
  • Used as an adjunct therapy with L-DOPA to achieve better balance between dopaminergic and cholinergic neurotransmission
44
Q

Describe how glycopyrrolate and propantheline bromide are used for GI disorders.

A
  • Quaternary amines
  • Used to treat GI spasms and peptic ulcers
  • Charged N makes crossing the gut difficult
45
Q

Explain how ipratropium is used to treat COPD.

A
  • Quaternary amine
  • M3 agonist: blocks acetylcholine-mediated constriction and opens the airways
  • Less effective as a monotherapy, but enhances the effect of β-adrenergic agonists in COPD
46
Q

Anticholinergic toxicity is largely ____________.

A

Dose-dependent

47
Q

What is the mneumonic device used to describe a toxic dose of atropine?

A
  • Red as a beef (flushed, scarlet skin)
  • Dry as a bone (dry mouth and skin, thirst)
  • Blind as a bat (blurred vision, obliterated irises)
  • Hot as a firestone (hot skin)
  • Mad as a hatter (hallucinations and delirium)
48
Q

Describe nicontic receptors.

A
  • Pentameric, ligand-gated ion channel
  • Acetylcholine binds and allows Na+ to flow in and depolarize the neuron
  • Located in parasympathetic and sympathetic postganglions (not a good target).
49
Q

If you can block nicotinic receptors, you can ____________.

A

Paralyze skeletal muscle

50
Q

How is skeletal muscle contraction triggered?

A
  1. Motor neurons in skeletal muscle come out of the spine
  2. Signal travels down the neuron and Ca+ enters
  3. Acetylcholine is released from vesicles into the motor endplate
  4. Nicotinic receptors are activated
  5. Na+ flows in and depolarizes the muscle, and triggers contraction
51
Q

List 4 clinical uses for nicotinic receptor antagonists.

A
  1. Muscle relaxation during surgery
  2. Tracheal intubation (to relax pharyngeal and laryngeal muscles)
  3. Control of ventilation (reduces chest wall resistance)
  4. Treatment of convulsions (sometimes used to alleviate peripheral component of convulsions associated with status epilepticus or local anesthetic toxicity; no CNS effect since these drugs don’t penetrate the blood-brain barrier)
52
Q

How do depolarizing competitive drugs work on nicotinic receptors?

A
  • They bind the nicotinic receptor and keep it in an open state, resulting in a constant influx of Na+ and persistent depolarization
  • Takes a long time to repolarize, and the receptor is unresponsive to new impulses at this time (think of a toilet flushing)
53
Q

How do nondepolarizing competitive drugs act on nicotinic receptors?

A

They bind nicotinic receptors and keep them in a closed state, with no Na+ influx (act as competitive inhibitors by blocking acetylcholine access)

54
Q

What is the only depolarizing competitive nicotinic receptor blocker?

A

Succinylcholine

55
Q

Phase I

A

Depolarization phase

56
Q

Phase II

A

Desensitization phase

57
Q

List the 5 nondepolarizing neuromuscular nicotine receptor blockers.

A
  1. d-turbcurarine
  2. Pancuronium
  3. Atracurium
  4. Rocuronium
  5. Mivacurium
58
Q

d-turbocurarine

A
  • Used as an anesthesia adjunct to provide muscle relaxation during surgery
  • Curare substituent: a Native American arrow poison
  • Not orally active; given parenterally (usually IV)
  • 30-60 minute duration of action
  • Overdose managed by maintaining respiration, or reversed by acetylcholinesterase inhibitors (i.e. neostigmine)
59
Q

Pancuronium

A

6x more potent than d-turbocurarine

60
Q

Atracurium, rocuronium, and micacurium

A
  • Used in surgery
  • Rapid-acting neuromuscular blockers (1-2 minutes)
  • High degree of flexibility in molecules
61
Q

List the 4 direct-acting cholinergic receptor agonist esters.

A
  • Acetylcholine
  • Carbachol
  • Methacholine
  • Bethanechol
62
Q

List the 3 direct-acting receptor agonist alkaloids and synthetic analogs.

A
  • (+)-muscarine
  • Pilocarpine
  • Nicotine
63
Q

Acetylcholine (+) + aspartic acid (-)

A

Ion pairing

64
Q

Acetylcholine + aromatic amino acids

A

Pi-cation interaction

65
Q

When does acetylcholine prefer the trans position?

A

Binding (especially in nicotinic receptors)

66
Q

When does acetylcholine prefer the cis confomation?

A

in solution

67
Q

Why is (+)-muscarine more potent than (-)-muscarine?

A

Because it has the same down hydrogen as muscarine

68
Q

How does varenicline tartrate help with smoking cessation?

A

Partial agonist; blocks nicotine from binding and is well-tolerated

69
Q

What are some side effects of varenicline tartrate?

A
  • GI (nausea, constipation, gas, vomiting)
  • Altered dreams
70
Q

How many basic nitrogens does nicotine have?

A

2

71
Q

Acetylcholine

A
  • Receptor: M,N
  • Cholinesterase sensitivity
  • Intraocular use for miosis during surgery
72
Q

Carbachol

A
  • Receptor: M,N
  • No cholinesterase sensitivity
  • Intraocular use for miosis during surgery, glaucoma
73
Q

Pilocarpine

A
  • Receptor: M
  • No cholinesterase sensitivity
  • Glaucoma
74
Q

Bethanechol

A
  • Receptor: M
  • No cholinesterase sensitivity
  • Urinary retention, post-operative ileus
75
Q

Varenicline

A
  • Receptor: N
  • No cholinesterase sensitivity
  • Smoking cessation

Spring 2020: P1 Therapeutics (12 decks)

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