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Part 3 – PM3B COPY T > (PM3B) Cholinergic Therapeutics > Flashcards

(PM3B) Cholinergic Therapeutics Flashcards

1
Q

Where does cholinergic transmission occur?

A

In the autonomic nervous system

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2
Q

What is the peripheral nervous system?

A

Output of CNS

Acts independently to regulate body’s internal environment

(1) Autonomic nervous system – ANS
(2) Somatic (motor) nervous system – SNS

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3
Q

What type of nerves control movement?

A

Efferent nerves of somatic (motor) nervous system

Innervate skeletal muscle

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4
Q

What type of nerves respond to external stimuli?

A

Afferent nerves of somatic (motor) nervous system

e.g. nociceptive fibres (pain-sensing)

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5
Q

What systems are in the autonomic nervous system (ANS)?

A

(1) Sympathetic nervous system
– Thoracic-lumbar output
– Synapase at ganglia either side of vertebral column
– Ganglia are distal to innervated tissue

(2) Parasympathetic nervous system
– cranial-sacral output
– Synapse at ganglia close to innervated tissue

(3) Enteric nervous system
– Neurones with cell bodies in intestine wall
– innervates GIT, pancreas, and gall bladder

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6
Q

Name some structures in the sympathetic nervous system.

A
  • eye
  • salivary glands
  • heart
  • lungs
  • adrenal medulla
  • liver
  • GIT
  • bladder
  • genitalia
  • blood vessels
  • sweat glands
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7
Q

Name some structures in the parasympathetic nervous system.

A
  • eye
  • lacrimal gland
  • salivary glands
  • heart
  • lungs
  • upper GIT
  • lower GIT
  • bladder
  • genitalia
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8
Q

What neurones are outside of the CNS in the autonomic nervous system?

A

(1) Preganglionic fibres
- arise from CNS synapse
- releases acetylcholine (ACh)
- cholinergic transmission

(2) Postganglionic nerve
- in ganglia
- terminate at the effector
- most release noradrenaline (NA)
- adrenergic transmission

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9
Q

Which type of neurones in the autonomic nervous system are responsible for cholinergic transmission?

A

Preganglionic fibres

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10
Q

Which type of neurones in the autonomic nervous system are responsible for adrenergic transmission?

A

Postganglionic nerves

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11
Q

How does the CNS act on skeletal muscle?

A

Binding of acetylcholine to nicotinic receptors

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12
Q

How does the CNS act on blood vessels?

A

Release of acetylcholine and binding to nicotinic receptors

Leads to release of noradrenaline

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13
Q

How does the CNS act on sweat glands?

A

Release of acetylcholine and binding to nicotinic receptors

Least to release of further acetylcholine and binding to muscarinic receptors

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14
Q

How does the CNS act on the adrenal medulla?

A

Release of acetylcholine and binding to nicotinic receptors

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15
Q

How does the CNS act on the salivary glands?

A

Release of acetylcholine and binding to nicotinic receptors

Least to release of further acetylcholine and binding to muscarinic receptors

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16
Q

Which nerves release ACh?

A

All postganglionic parasympathetic nerves
- to act on mAChRs

All motor nerves
- to act on nAChRs

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17
Q

Where are M1 receptors located?

A

Ganglia in CNS

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18
Q

Where are M2 receptors located?

A

Cardiac

CNS

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19
Q

Where are M3 receptors located?

A

Glands + smooth muscle + blood vessels

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20
Q

Where are M4 receptors located?

A

CNS

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21
Q

Where are M5 receptors located?

A

CNS

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22
Q

What is the function of M1 receptors?

A

Excitation + secretion

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23
Q

What is the function of M2 receptors?

A

Cardiac + CNS inhibition

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24
Q

What is the function of M3 receptors?

A

Secretion

Contraction

Vasodilatation

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25
Q

What is the function of M4 receptors?

A

Enhanced movement

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26
Q

What is the function of M5 receptors?

A

Unknown

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27
Q

Which G protein does an M1 receptor act on?

A

G-alpha q

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28
Q

Which G protein does an M2 receptor act on?

A

G-alpha- i/o

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29
Q

Which G protein does an M3 receptor act on?

A

G-alpha q

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30
Q

Which G protein does an M4 receptor act on?

A

G-alpha- i/o

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31
Q

Which G protein does an M5 receptor act on?

A

G-alpha q

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32
Q

What is the response following binding of an M1 receptor?

A

Increased IP3

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33
Q

What is the response following binding of an M2 receptor?

A

Decreased cAMP

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34
Q

What is the response following binding of an M3 receptor?

A

Increased IP3

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35
Q

What is the response following binding of an M4 receptor?

A

Decreased cAMP

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36
Q

What is the response following binding of an M5 receptor?

A

Increased IP3

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37
Q

What is the effect of binding to a muscarinic receptor eliciting an effect on a G-alpha q G protein?

A

Increased IP3

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38
Q

What is the effect of binding to a muscarinic receptor eliciting an effect on a G-alpha i/o G protein?

A

Decreased cAMP

39
Q

Name some agonists of muscarinic receptors.

A

(1) Acetylcholine
(2) Carbachol
(3) Oxotremorine
(4) Pilocarpine
(5) Bethanechol

40
Q

What are some antagonists of an M1 receptor?

A

(1) Atropine

(2) Pirenzepine

41
Q

What are some antagonists of an M2 receptor?

A

Atropine

42
Q

What are some antagonists of an M3 receptor?

A

(1) Atropine

(2) Darifenacin

43
Q

What are some antagonists of an M4 receptor?

A

Atropine

44
Q

What are some antagonists of an M5 receptor?

A

Atropine

45
Q

What are some general effects of muscarinic receptor agonists?

A

(1) Bradycardia/ reduced cardiac output
(2) Vasodilation

(3) Increased secretion
- salivation
- lacrimation
- sweating

(4) Bronchoconstriction + increased bronchial secretion
(5) Increased gut motility

(6) Reduction of intraocular pressure
- a result of pupillary constriction

46
Q

When is an mAChR agonist used in glaucoma?

A

A mitotic (pilocarpine) used to reduce intraocular pressure

Action lasts ~1 day

47
Q

When is an mAChR agonist used in urinary retention?

A

Bethanechol

To relieve urinary retention

48
Q

When is an mAChR agonist used in constipation?

A

Bethanechol

Increase gut motility

49
Q

What is the acronym SLUDGE in regard to mAChRs?

A 
S = salivation
L = lacrimation
U = urination (relaxation of internal sphincter + contraction of detrusor muscles)
D = defecation
G = gastrointestinal upset
E = emesis (vomiting)
50
Q

What is emesis?

A

Vomiting

51
Q

Why is therapeutic use of mAChRs limited?

A

Causes SLUDGE

52
Q

What are some actions of mAChR antagonists?

A

(1) Block secretion
- salivary
- lacrimal
- sweating
- bronchial

(2) Tachycardia
(3) Pupillary dilation
(4) Inhibition of gut motility
(5) Bladder paralysis
(6) Smooth muscle relaxation (except gut)
(7) Excitatory CNS effects

53
Q

What can blocked secretion, due to use of mAChR antagonists, lead to?

A

Dry mouth

54
Q

What can pupillary dilation, due to use of mAChR antagonists, lead to?

A

Increased intraocular pressure

55
Q

What can inhibition of gut motility, due to use of mAChR antagonists, lead to?

A

Constipation

56
Q

What can paralysis of the bladder, due to use of mAChR antagonists, lead to?

A

Urinary retention

57
Q

What can the excitatory effects on the CNS, due to use of mAChR antagonists, lead to?

A

Disorientation

Mood swings

58
Q

When are mAChR antagonists used for ophthalmic purposes?

A

(1) Tropicamide
- to dilate pupils (mydriasis)
- to aid eye examinations

(2) Atropine/ cyclopentolate
- to paralyse the eye
- to treat inflammation

59
Q

When are mAChR antagonists used for bronchodilation purposes?

A

(1) Ipratropium
- orally inhaled aerosol
- short-acting
- half-life 2-4 hours
- acute asthma

(2) Tiotropium
- orally inhaled aerosol
- half-life ~10 hours
- long-acting
- COPD

60
Q

When are mAChR antagonists used for reducing intestinal motility?

A

(1) Atropine/ dicycloverine
- smooth muscle relaxant
- anti-spasmodic agents
- management of IBS
- management of diverticular disease (presence of pouches in wall of intestine)

61
Q

When are mAChR antagonists used for treating urinary incontinence?

A

(1) Tolterodine/ oxybutynin
- treatment of OAB (overactive bladder)
- extended-release formulation OD

Ideally want a selective M3 antagonist such as darifenacin/ solifenacin

62
Q

When are mAChR antagonists used for cardiovascular purposes?

A

(1) Atropine
- bradycardia
- after MI

63
Q

When are mAChR antagonists used for nausea and vomiting?

A

(1) Hyoscine
- transdermal patch
- orally
- treatment of motion sickness
- acts on ‘vomiting centre’ of hind brain medulla

64
Q

When are mAChR antagonists used for Parkinson’s disease?

A

(1) Trihexyphenidyl hydrochloride
- treatment of dopamine deficiency
- due to overactivity of cholinergic transmission

65
Q

When are mAChR antagonists used for anaesthesia?

A

(1) Atropine/ hyoscine
- inhibition of salivation/ bronchial secretion
- cause drowsiness

(2) Atropine/ glycopyrronium
- during surgery
- prevent vagal inhibition of the heart

66
Q

What is the function of nicotinic receptor subtypes?

A

Excitation

67
Q

Where are nicotinic receptors in muscle located?

A

Postsynaptic

Neuromuscular junction (NMJ)

68
Q

Where are nicotinic receptors in ganglia located?

A

Postsynaptic ganglia

69
Q

Where are nicotinic receptors in CNS located?

A

Pre- and post- synaptic

70
Q

What are some agonists of nicotinic receptors located in muscle?

A

(1) Acetylcholine

(2) Succinylcholine

71
Q

What are some agonists of nicotinic receptors located in ganglia?

A

(1) Acetylcholine

(2) Nicotine

72
Q

What are some agonists of nicotinic receptors located in the CNS?

A

(1) Acetylcholine

(2) Nicotine

73
Q

What are some antagonists of nicotinic receptors located in muscle?

A

(1) Tubocurare

(2) Pancuronium

74
Q

What are some antagonists of nicotinic receptors located in ganglia?

A

(1) Trimetaphan

(2) Hexamethonium

75
Q

What are some antagonists of nicotinic receptors located in the CNS?

A

Mecamlylamine

76
Q

Why are most nicotinic acetylcholine ligands therapeutically undesirable?

A

Lack of selectivity between sympathetic + parasympathetic ganglia

77
Q

What effects do the ganglion-blocking drugs trimetaphan and hexamethonium have?

A

(1) Cardiovascular
- block of sympathetic system
- vasodilation causes fall in BP
- trimetaphan used to induce hypotension in surgery

(2) GIT
- block of parasympathetic system
- inhibition of motility

(3) Genito-urinary system
- block of parasympathetic system
- impairment of micturition (urination)

78
Q

How do neuromuscular blocking agents work?

A

(1) Competitive antagonists
- widely used as muscle relaxants
- adjunct to anaesthesia
- e.g. pancuronium, vecuronium, atracurium

(2) Agonists which cause a depolarising block of muscle endplate (depolarising blockers)
- to cause paralysis during anaesthesia
- e.g suxamethonium (succinylcholine)

79
Q

What are the stages of cholinergic transmission?

A

(1) Acetyl CoA + choline produce ACh in the presence of CAT
(2) ACh is packaged into vesicles and released into synaptic cleft
(3) Binds to mAChR or nAChR on postsynaptic membrane to elicit a cellular effect

80
Q

What happens to excess ACh in the synaptic cleft?

A

(1) Broken down into choline + acetate by acetylcholinesterase
(2) Endocytosis of choline + acetate

81
Q

Name a drug that prevents vesicle release in cholinergic transmission.

A

Botulinum toxin

82
Q

Name some therapeutic acetylcholinesterases.

A

(1) Donepezil
(2) Galantamine
(3) Rivastigmine

83
Q

What is the function of vesamicol?

A

Block packaging of ACh into vesicles

84
Q

What is the function of hemicholinium?

A

Blocks choline reuptake

85
Q

What is the function of botulinum toxin type A?

A

Blocks vesicle docking/ release

Causes dry mouth/ blurred vision

Can lead to respiratory paralysis

86
Q

What are some therapeutic applications of botulinum toxin?

A

(1) Muscle spasm
- focal dystonic spasms (writer’s cramp)
- spasmodic dystonia
- pain associated with continual muscle contraction

(2) Migraine/ headache
- facial muscle contractions causing headaches

(3) Excessive secretion
- severe underarm sweating
- severe salivation
- when not managed effectively with topical agents
- can be effective for 6-10 months

87
Q

What amino acid binding sites are present in cholinesterase?

A

(1) Histidine - catalytic (active) site
(2) Serine
(3) Glutamate - allosteric (anionic) site

88
Q

What are the main classes of anticholinesterase?

A

(1) Short-acting
- e.g. edrophonium

(2) Medium-duration
- e.g. neostigmine/ pyridostigmine

(3) Irreversible
- e.g. ecothiopate

89
Q

What is the mechanism of action of neostigmine?

A

Inhibits cholinesterase

Binds to serine of cholinesterase

90
Q

What is myasthenia gravis?

A

Autoimmune disease

Leads to depletion of nAChRs at NMJ

Use of neostigmine/ pyridostigmine as they are able to cross BBB

91
Q

What are some therapeutic uses of anticholinesterases?

A

(1) Myasthenia gravis
(2) Dementia
(3) Reversal of competitive neuromuscular block after anaesthesia

92
Q

Why are anticholinesterases used for treatment of dementia?

A

Alzheimer’s is associated with loss of cholinergic neurones in basal forebrain

Donepezil, rivastigmine + galantamine used to treat mild-moderate AD

93
Q

What anticholinesterases are used for reversal of competitive neuromuscular block after anaesthesia?

A

(1) Edrophonium - transient action

(2) Neostigmine

Part 3 – PM3B COPY T (33 decks)

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