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Neuropharmacology > Lecture 6 > Flashcards

Lecture 6 Flashcards

1
Q

What are the subtypes of mAChRs?

A

M1, M2, M3, M4, M5

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2
Q

What is the function of the M1 subtype?

A
  • neural - modulation of ganglionic transmission
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3
Q

Where is the M1 subtype expressed?

A

Autonomic ganglia

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4
Q

What is the function of the M2 subtype?

A
  • cardiac - cardiac slowing - decreases force of contraction
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5
Q

Where is the M2 subtype expressed?

A

Cardiac atria and conducting tissue

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6
Q

What is the function of the M3 subtype?

A
  • glandular - secretion of saliva - increases gut motility
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7
Q

Where is the M3 subtype expressed?

A

Salivary glands and smooth muscles of gut

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8
Q

What is the function of the M4 and M5 subtype?

A

Modulation of synaptic transmission

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9
Q

Where are the M4 and M5 receptors expressed?

A

CNS (substantia nigra for M5)

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10
Q

What G protein subtype do M1, 3 and 5 subtypes bind to?

A

G𝛼q

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11
Q

What are the typical second messengers of G𝛼q?

A
  • Protein Kinase C (PKC) - Ca2+
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12
Q

What are the physiological responses of G𝛼q activation?

A
  • excitation - secretion - contraction
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13
Q

What G protein subtype do M2 and 4 subtypes bind to?

A

G𝛼I

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14
Q

What are the typical second messengers of G𝛼i?

A
  • (Reduced activity of) cAMP and PKA - Gβ𝛾 opens K+ channels
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15
Q

What are the physiological responses of G𝛼i activation?

A
  • inhibition - reduced force/rate of contraction
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16
Q

What are the mechanisms of G𝛼q activation?

A

1) stimulates phospholipase C β (PLCβ) 2) breaks down PIP2 to diacylglycerol (DAG) and IP3 - DAG activates PKC - IP3 causes influx of Ca2+

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17
Q

What are the mechanisms of G𝛼i activation?

A

1) inhibits adenylate cyclase (AC) 2) reduction in cAMP, PKA activation and Ca2+ activity 3) Gβ𝛾 activates K+ channels leading to an efflux from the cell - hyperpolarisation and reduced excitability

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18
Q

Is this the activity of G𝛼q or G𝛼i?

A

G𝛼q

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19
Q

Is this the activity of G𝛼q or G𝛼i?

A

G𝛼I

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20
Q

What are parasympathomimetics?

A

Agonists of parasympathetic systems

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21
Q

List physiological effects of mAChR agonists

A
  • constriction of circular muscle of iris and cilliary muscle of eye - increases secretion (salivation, sweating) - bronchostriction and mucus production - increased gut motility and relxation of sphincter - bladder constriction and relxation of sphincter - vasodilation= decreased BP and HR
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22
Q

Name examples of mAChR agonists

A
  • carbachol - pilocarpine - cevimeline - bethanechol
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23
Q

List the clinical uses of mAChR agonists

A
  • dry mouth (Xerostomia) and dry eyes (Sjögren’s syndrome)= Cevimeline - eye drops for glaucoma (decrease intra ocular pressure by constricting muscles)= Pilocarpine - promote activity of smooth muscle of GI and urinary tract (bethanechol)
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24
Q

What are parasympatholytics?

A

Antagonists of parasympathetic systems

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25
Q

What is an example of an mAChR antagonist?

A

Atropine

26
Q

List the physiological effects of mAChR antagonists

A
  • dilated pupils (loss of focusing) - decreased secretion of tears- reduced sweating (dry skin and increased body temperature) - reduced gut motility (constipation) - reduced saliva production - increased heart rate (tachycardia) - relaxation of bladder - bronchodilation, relxation of airway smooth muscle - reduced bronchial secretions
27
Q

List the clinical uses of mAChR antagonists

A
  • eye exams= tropicamide - diarrhoea treatment= co-phenotrope - chronic bronchitis= ipratropium and oxitropium - tremor and rigidity in Parkinson’s= CNS benzhexol - adjunct to anaesthesia - reversal of neuromuscular blockade and nerve gas poisoning
28
Q

What is the myth of the M1 receptor in gastric acid secretion?

A

No less GA secretion in response to carbachol in KO M1 receptor compared to normal wild type mice

29
Q

What do we see when pirenzipine is used in mice with KO M1 receptors?

A

Gastric acid secretion is blocked even in mice lacking M1 receptors

30
Q

When does pirenzipine block gastric acid and histamine secretion?

A

When the M3 receptor gets antagonised

31
Q

What are the two types of cholinesterases?

A
  • true acetylcholinesteraste - pseudo-cholinesterase (butyryl/plasmacholinesterase)
32
Q

Where are true acetylcholinesterases found?

A
  • cholinergic synapses - bound to postsynpatic membrane in the synaptic cleft
33
Q

Where are pseudo-cholinesterases found?

A
  • widely distributed in plasma
34
Q

Why are pseudo-cholinesterases important?

A

Inactivate depolarising blockers e.g. suxamethonium

35
Q

What are true and psuedo cholinesterases inhibited by?

A

Clinically relevant anticholinesterases

36
Q

What are the three classes of anticholinesterases?

A
  • alchohol - carbamate - organophosphate
37
Q

What is an example of an alchohol anticholinesterase?

A

Edrophonium

38
Q

What are examples of carbamate anticholinesterases?

A
  • neostigmine - pyridostigmine - physostigmine
39
Q

What are examples of organophosphate anticholinesterases?

A
  • dyflos - ecothiopate - parathion (P=S)
40
Q

What is an example of a reversible anticholinesterase?

A

Neostigmine

41
Q

What is an example of an irreversible anticholinesterase?

A

Dyflos

42
Q

How does neostigmine work?

A

1) sits in the catalytic pocket of the cholinesterase 2) carbamylates serine residue 3) inactivates cholinesterase 4) inactivation= carbamyl-serine hydrolysed

43
Q

How does dyflos work?

A

1) phosphorylates serine residue 2) covalently bound - hydrolysis is difficult - oximes can bind to anionic site and can phosphorylate themsleves - frees serine= cholinesterase reactivated

44
Q

Why is ageing a problem for reactivating cholinesterases?

A
  • ageing= ageing of the bound between the phosphate group and serine residue - longer you wait to deliver oxime= more difficult it is to reactivate cholinesterase
45
Q

Use of neostigmine

A

Reversal of neuromuscular paralysis

46
Q

Use of edrophonium

A

Diagnosis of myasthenia gravis

47
Q

Use of neostigmine and pyridostigmine

A

Treatment of myasthenia gravis

48
Q

Use of physostigmine and ecothiopate

A

Treatment of glaucoma (previously)

49
Q

Use of donepzil, galantamine, and rivastigmine

A

Alzheimer’s disease

50
Q

What are the physiological effects of anticholinesterases?

A
  • increased ACh activity at autonomic NEJ, NMJ and CNS - increased secretion (salivary, lacrimal, bronchial, GI glands) - increased peristaltic activity (stimulant laxatives)
51
Q

What are side effects of anticholinesterases?

A
  • depolarisation block at NMJ - bronchoconstriction - bradycardia and hypotension - convulsions, respiratory failure and unconsciousness of the CNS
52
Q

What are the components of the cholinergic hypothesis of Alzheimer’s disease?

A
  • loss of cholinergic neurones - loss of muscarinic receptors - loss of nicotinic receptors - reduction in vesicular ACh transporters
53
Q

Why would you use an AChE inhibitor for Alzheimer’s disease?

A
  • reduce brain AChE activity - AChE inhibitors improve cognitive performance in the early stages of Alzheimer’s
54
Q

What is myasthenia gravis?

A
  • autoimmune disease - characterised by a loss of NMJ nAChRs and NMJ structure - muscular weakness and paralysis
55
Q

What would you expect when you give a patient with myasthenia gravis an anti-AChE?

A

Reversal of symptoms

56
Q

What are the three categories of organophosphates?

A
  • G agents - V agents - A agents
57
Q

Name three drugs used to reverse organophosphate effects?

A
  • atropine - oximes e.g. pralidoxime - valium
58
Q

Why would you use atropine to reverse nerve agent effects?

A

Counteract effects of excessive mAChR stimulation

59
Q

Why would you use oximes to reverse nerve agent effects?

A

Reactivates AChE so acts as an antidote

60
Q

Why would you use valium to reverse nerve agent effects?

A
  • used for seizures - reversible antiAChEs as prophylactics against nerve agents

Neuropharmacology (15 decks)

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