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ESA 5 - Pharmacology > Non-Steroidal Anti-Inflammatory Drugs > Flashcards

Non-Steroidal Anti-Inflammatory Drugs Flashcards

1
Q

How many drugs are there in the NSAID class?

A

About 50

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2
Q

Do the drugs in the NSAID class show structural homogenity?

A

No, there is significant heterogeneity, and the drugs have different potencies and different efficacies

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3
Q

What is the principle action of NSAIDs?

A

They act on key enzymes in prostaglandin synthesis

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4
Q

What are the primary therapeutic effects of NSAIDs?

A
  • Analgesia
  • Anti-inflammatory
  • Antipyretic
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5
Q

What does local injury result in?

A

A signalling response provided by many autocoids

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6
Q

What are the features of the local response to injury?

A
  • Rapid
  • Focused
    Integrated
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7
Q

What is the inflammatory response?

A

A fundamental response of the body to injurous stimuli

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8
Q

What injuries can cause an inflammatory response?

A
  • Physical/chemical injury
  • Structural strain
  • Infections
  • Many diseases
  • Autoimmune conditions
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9
Q

What is the advantage of the inflammatory response?

A

It is normally a protective response to reduce the risk of further damage to the organism

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10
Q

How does the inflammatory response alert the body to damage?

A

Through signalling pain

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11
Q

What is the importance of the inflammatory response signalling damage through pain?

A

It reduces the risk of further damage through continued use/activity

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12
Q

What are autocoids?

A

A diverse range of local molecular mediators and signalling agents employed

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13
Q

Give 7 examples of autocoids

A
  • Bradykinins
  • Histamine
  • Cytokines
  • Leukotrienes
  • Nitric oxide
  • Neuropeptides
  • Eicosanoids
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14
Q

What class of molecules do eicosanoids include?

A

Prostaglandins

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15
Q

What does signalling overlap with autocoids ensure?

A

A robust inflammatory response

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16
Q

What are the key features of autocoids?

A
  • Localised release
  • Short half life
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17
Q

What does the localised release and short half life of autocoids allow for?

A

Fine control of the signalling response

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18
Q

What are eicosanoids? C

A

20C phospholipid derivatives used as signalling molecules

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19
Q

What gives rise to different classes of eicosanoids?

A

Variation in synthetic routes

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20
Q

What are prostanoids?

A

A subclass of eicosanoids

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21
Q

Give 3 examples of prostanoids

A
  • Prostaglandins
  • Prostacyclins
  • Thromboxanes
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22
Q

What are eicosanoids derived from?

A

Arachidonic acid

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23
Q

Where does arachidonic acid come from?

A

It is cleaved from cell membrane phospholipids

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24
Q

What enzyme cleaves arachidonic acid from cell membrane phospholipase?

A

Phospholipase A2

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25
Q

What happens to arachidonic acid in the synthesis of prostaglandins?

A

COX-1/COX-2 enzymes convert it to prostaglandin G

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26
Q

What happens to PG G in the synthesis of prostaglandins?

A

COX-1/COX-2 enzymes convert it to prostaglandin H

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27
Q

What happens to PG H in the synthesis of prostaglandins?

A

It is converted to specific PG enzymes - PGs D, E, F, I

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28
Q

What is the most important prostaglandins in mediating the inflammatory response?

A

E

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29
Q

What is prostaglandin E responsible for?

A
  • Vasodilation
  • Hyperalgesia
  • Fever
  • Immunomodulation
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30
Q

Where is COX-1 expressed?

A

In a wide range of tissue types

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31
Q

Describe the expression of COX-I

A

Constituitive - expressed all the time

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32
Q

What is the importance of PG synthesis by COX-I?

A

It has a major cytoprotective role in;

  • The gastric mucosa
  • The myocardium
  • The renal parenchyma

It also ensures optimised local perfusion

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33
Q

How do prostaglandins ensure optimised local perfusion?

A

It ensures vasodilation, and so ensures delivery of nutrients

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34
Q

What is the clinical relevance of the cytoprotective role of prostaglandins in the GI tract?

A

A major ADR of long term NSAIDs is a reduction in mucus and therefore damage to underlying tissue

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35
Q

What is the half life of prostaglandins?

A

10 minutes

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36
Q

What is the result of the short half life of prostaglandins?

A

It needs constant synthesis

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37
Q

Why are most ADRs of NSAIDs due to COX-1 inhibition?

A

Due to its constitutive expression

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38
Q

What is COX-2 expression induced by?

A

Inflammatory mediators, such as bradykinin

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39
Q

Where is COX-2 consitutively expressed?

A

In parts of brain and kidney

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40
Q

How do the main therapeutic effects of NSAIDs occur?

A

Via COX-2 inhibition

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41
Q

Do COX-1 and 2 work independantly?

A

No

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42
Q

What is PG synthesis with COX-1 and -2 depedant on?

A

Tissue and organ type

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43
Q

How does prostaglandin synthesis occur with COX-1?

A

It has a hydrophpobic channel, where arachinodic acid enters and gets catalysed to prostaglandins

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44
Q

What kind of drugs fit into the mouth of COX-1?

A

Small, sharp, aspirin-like drugs

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45
Q

What kind of drugs can fit in the mouth of COX-2?

A
  • Small, sharp, aspirin-like drugs
  • Big, blunt drugs
46
Q

What receptors do prostaglandins bind with?

A

GPCRs

47
Q

What do the specific actions of prostaglandins depend on?

A

The receptor types

48
Q

What are the main types of receptors for PG E?

A

EP1-4

49
Q

What does the action of prostaglandins often include?

A

Synergising effects of other autocoids, e.g. bradykinin and histamine

50
Q

Which prostanoid in particular is released post-injury?

A

PGE2

51
Q

Where are autocoids and prostanoids released from post injury?

A

Local tissues and blood vessels

52
Q

What does autocoid release induce?

A

Expression of COX-2

53
Q

What do autocoids synergise with?

A

Other autocoids, e.g. bradykinin and histamine

54
Q

Do prostaglandins act as vasoconstrictors or vasodilators?

A

They are potent vasodilators

55
Q

Do prostaglandins increase the capillary permeability?

A

Not directly, but they synergise permeating effects of bradykinin/histamine

56
Q

Which prostaglandin receptors are responsible for vasodilation?

A

EP2 (Gs)

57
Q

Which prostaglandin receptors are responsible for increased peripheral nociception?

A

EP1 (Gq)

58
Q

What are painful stimuli carried by?

A

Afferent C fibres

59
Q

What happens to the surrounding tissue following trauma/injury?

A

Surrounding tissue and neurones synthesis prostaglandins - PGE2 in particular. Other autcoids are also released, notably bradykinin

60
Q

What happens to the PGE2 released in response to trauma/injury?

A

It binds with C fibre neuronal EP1 GPCR

61
Q

What does GPCR activation by PGE2 in pain cause?

A
  • Increased neuronal sensitivity to bradykinin
  • Inhibition of K+ channels
  • Increased Na+ channel sensitivity
62
Q

What is the result of inhibition of K+ channels by PGE2?

A

Neurone tends to be more polarised

63
Q

What is the result of increased Na+ channel activity caused by PGE2 in pain?

A

It increases the likelihood of C fibres firing in response to moderate stimulation

64
Q

What do the actions of GPCR activation by PGE2 in pain do in combination?

A

Act to increase C fibre activity

65
Q

What might prostaglandins do to previously silent C fibres?

A

Activate them

66
Q

How does peripheral sensitisation occur?

A

EP I binding leads to increased C fibre activity

Other autocoids are involved in increasing sensivity

67
Q

What is EP1?

A

A Gq GPCR

68
Q

What does activation of EP I lead to?

A

Increase in intracellular calcium, therefore increased neurotransmitter release

69
Q

What is allodynia?

A

The sensitisation of receptors to cause pain signalling In response to normally non-stimulating stimulus intensity i.e. non-painful things are painful

70
Q

What does increased sustained nociceptive signalling peripherally result in?

A

Increased cytokines levels in the dorsal horn cell body

71
Q

What does increased cytokine levels in the dorsal horn cell body lead to?

A

Increased COX-2 synthesis and therefore increased PGE2 synthesis

72
Q

What is the effect of the increased PGE2 produced due to increased sustained nociceptive signalling peripherally?

A

It acts via a local GPCR EP2 (GS type) to increase the sensitivity and discharge rate of secondary interneurones by incresaing cAMP and PKA

im not 100% sure on this lol

73
Q

What is one aspect of the increase in sensitivity and discharge rate of secondary interneurones?

A

Removal of glycinergic inhibition

74
Q

What do bacterial endotoxins do in infected/inflammatory states?

A

They stimulate macrophage release of IL-I

75
Q

What happen as a result of IL-I release in infected/inflammatory states?

A

It acts within the hypothalanus to stimulate PGE2 synthesis via the induction of COX-2

76
Q

What receptor is involved in pyrexia due to PGE2?

A

EP3

77
Q

What kind of receptor is EP3?

A

Gi type GPCR

78
Q

What is the result of PGE2 stimulation of EP3 receptors?

A

Results in increased heat production and decreased heat loss

79
Q

Why does pyrexia even happen in infection like what is the point

A

it makes the body less pleasant for bacterial infection

80
Q

transition to no caps for speed cus literally cba with this

A

ok

81
Q

how are the main therapeutic effects of nsaids acheived

A

cox-2 inhibition

82
Q

how is the pharmaclogical action of nsaids achieved

A

competitive inhibition of cox-1 and 2

nearly all not all

83
Q

how do nsaids competitively inhibit cox1/2

A

occupation of cox 1/2 hydrophobic channel by nsaid competes with AA site occupation

84
Q

how many diff types of nsaids are there

A

about 50

85
Q

what is different about the diff types of nsaids

A

affinity

efficacy

cox1/2 selectivity

86
Q

what do nearly all nsaids have therapeutic efficacy as

A

analgesics

anti inflammatories

antipyreics

87
Q

what determines the choice of nsaid

A

dominant disease state

patients level of pain

individual patient response

88
Q

how are nsaids administered

A

typically orally, but many topical preperations for soft tissue injuries

89
Q

what is good about topical nsaids

A

can get very high penetration, and therefore safer than oral for given amount of pain relief as lots of drugs gets only to the site you want to treat

90
Q

what kind of pharmacokinetics do nsaids have

A

linear, but only within therapeutic dose ranges

91
Q

what is the half life of nsaids

A

nsaids can be divided into 2 groups based on their half life - <6 hours and >10 hours

92
Q

what are nsaids that have a half life of <6 hours good for

A

acute pain

93
Q

what are nsaids that have a half life of >10 hours good for

A

chronic pain - only need one tablet a day

94
Q

are nsaids protein bound?

A

many are heavily protein bound, 90-99%

95
Q

what are the main therapeutic uses of nsaisds

A

anti inflammatories

analgesia

96
Q

describe the use of nsaids as anti-inflammatories

A

very wide use in msk disorders, e.g. ra and osteoarthritis

97
Q

what are nsaids used for in analgesia

A

mild to moderate pain

98
Q

how do nsaids compare to opiates

A

they are less effective, but have a better adr proflie

99
Q

what leads to the side effects of nsaids

A

inhibition of cox-1 constitutive pg synthesis

100
Q

what is long term use of nsaids in the elderly associated with

A

iatrogenic morbiditiy and mortality

101
Q

where are the major adrs of nsaids seen

A

in the stomach/gi tract

102
Q

When do renal ADRs occur with nsaids

A

in compromised individuals with HRH or hypovolaemia

103
Q

what % of nsaid users have gi adrs

A

35%

104
Q

are gi adrs in nsaid users always symptomatic?

A

no, often asymptomatic

105
Q

what are the gi adrs of nsaids

A

varying degrees of stomach pain, nausea, heartburn, gastric bleeding, and ulceration

106
Q

how do nsaids cause gi adrs

A

gastric cox-1 pge2;

  • stimulates cytoprotective mucus secretion throughout the gi tract
  • reduces acid secretion
  • promotes mucosal blood flow
107
Q

how can the adrs of nsaids be offset?

A

PPIs or misoprostol

108
Q

why can nsaids lead to renal adrs

A

because pge2 and pgi2 maintain renal blood flow. if reduced by nsaids, then gfr decreases, and therefore risk of renal compromise

109
Q

what follows renal compromise caused by nsaids

A

na k cl and water retention with increaed likelihood of hypertension

110
Q

What is the difference between allodynia and spontaneous pain?

A

Spontaenous pain occurs without a stimulus

111
Q

What do allodynia and spontaneous pain have in commmon?

A

They both cause hyperalgesis - pain at a normally non-stimulating level of stimulus intensity

ESA 5 - Pharmacology (28 decks)

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