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ESA 5 - Pharmacology NEW > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

What are non-steroidal anti-inflammatory (NSAIDs) used for?

A
  • In isolation, to treat mild to moderate pain
  • In combination, to treat chronic pain from inflammation
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2
Q

Give an example of chronic pain NSAIDs can be used to treat?

A

Pain from RA

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3
Q

What is the physiological importance of the inflammatory process?

A

It is a fundamental response to injourious stimulus, acting as a protective mechanism to reduce the risk of further damage to the organism

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4
Q

What is used to show their is tissue damage and thus stimulate the inflammatory process?

A

Autocoids

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5
Q

What are autocoids?

A

A wide range of local molecular mediators and signalling agents

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6
Q

What autocoids do NSAIDs act on?

A

Prostaglandins

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7
Q

What pathway is prostaglandin synthesis part of?

A

The arachidonic acid metabolism pathway

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8
Q

What is arachidonic acid produced from?

A

Phospholipids from the membrane

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9
Q

How is arachidonic acid produced from phospholipids from the cell membrane?

A

Mainly via phospholipase A2

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10
Q

What happens to the arachidonic acid produced from phospholipids from the cell membrane?

A

They can either enter the prostaglandin pathway or the leukotriene pathway

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11
Q

What does the prostaglandin pathway involve?

A

Metabolism by COX-1 and COX-2 enzymes to produce PGH

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12
Q

What happens once PGH has been produced in the prostaglandin pathway/

A

Specific prostaglandins can be produced from this

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13
Q

What is the most inmportant prostaglandin produced from PGH in the prostaglandin pathway?

A

PGE

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14
Q

What do prostaglandins bind to?

A

GPCRs

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15
Q

What does the action of prostaglandins when binding to GPCRs depend on?

A

The receptor types

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16
Q

What are the receptors for PGE?

A

EP1-4

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17
Q

Broadly, what happens when prostaglandins bind to GPCRs?

A

Autocoid release

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18
Q

What effect does prostaglandin induced autocoid release have?

A

Will induce the expression of COX-2

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19
Q

What effect do prostaglandins have on other autocoids?

A

They synergise them

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20
Q

What is the result of prostaglandins have a synergistic action on other autocoids?

A

It means that there is a positive feedback loop mechanism present with prostaglandin production

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21
Q

What do prostaglandins act to do?

A

Induce pain and pyrexia

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22
Q

How do prostaglandins act to produce pain?

A
  • By sensitising peripheral nociception
  • By sensitising central nociception
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23
Q

How do prostaglandins sensitise peripheral nociception?

A
  • PGE2 can bind to EP1 in C-fibres
  • Rise in [Ca2+]i levels
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24
Q

What kind of GPCR is EP1?

A

Galphaq-type

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25
Q

What does PGE2 binding to EP1 in C-fibres cause?

A
  • Inhibition of K+ channels
  • Increase in Na+ channel expression
  • Increase in neuronal sensitivity to bradykinin
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26
Q

What is the overall result of PGE2 binding to EP1?

A

Increase in C-fibre activity

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27
Q

What is the result of increase in [Ca2+]i levels caused by PGE2 binding to EP1?

A

Increased neurotransmitter release

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28
Q

How do prostaglandins sensitise central nociception?

A

PGE2 can bind to EP2 in the dorsal horn of the spinal cord

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29
Q

What kind of GPCR is EP2?

A

Galphas-type

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30
Q

What does PGE2 binding to EP2 in the dorsal horn of the spinal cord cause?

A

A rise in cAMP, and subsequent action of PKAs, causing a reduction in glycine receptor binding affinity, leading to increased pain reception

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31
Q

What does glycine act as?

A

An inhibitor of neuronal activity

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32
Q

What is the effect of macrophage release of IL-1 at inflammatory sites?

A

It stimulates the hypothalamus to stimulate PGE2 release

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33
Q

What is the result of PGE2 release caused by macrophage release of IL-1?

A

It acts on EP3, causing a fall in cAMP which eventually causes an increase in [Ca2+]i levels in the neurones regulating temperature

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34
Q

What kind of GPCR is EP3?

A

Galphai-type

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35
Q

What is the result of the effect of PGE2 on neurones regulating temperature?

A
  • Increased heat production
  • Reduced heat loss
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36
Q

What do COX enzymes do?

A

Catalyse the reaction converting arachidonic acid to PGH

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37
Q

What is the difference between COX-1 and COX-2, regarding expression?

A

COX-1 expressed in wide range of tissues and is constitutively expressed. COX-2 is only expressed via induction by inflammatory mediators, and so is only expressed during injourious stimuli

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38
Q

Give an example of an inflammatory mediator that can induce the expression of COX-2

A

Bradykinin

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39
Q

What is the role of COX-1?

A

It has a major cytoprotective role

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40
Q

Where does COX-1 have a major cytoprotective role?

A
  • Gastric mucosa
  • Myocardium
  • Renal parenchyma
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41
Q

How does COX-1 perform its cytoprotective role?

A

It ensures local perfusion

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42
Q

What is the half life of COX-1?

A

10 minutes

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43
Q

What is the result of COX-1 having a short half life?

A

There is a need for its constant synthesis

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44
Q

What drugs fit into the mouth of COX-1?

A

Small, sharp, asprin like drugs

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45
Q

What drugs fit into the mouth of COX-2?

A

Both short, sharp asprin like drugs, and big, blunt drugs

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46
Q

What produces the main therapeutic effects of NSAIDs?

A

COX-2 inhibition

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47
Q

What are the main ADRs of NSAIDs caused by?

A

COX-1 inhibition

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48
Q

Do COX-1 and 2 enyzmes work independantly?

49
Q

What is PG synthesis from COX-1 and 2 dependant on?

A

Tissue and organ type

50
Q

What is the mechanism of action of the majority of NSAIDs?

A

Competitive inhibition of the COX-1 and COX-2 arachidonic acid binding sites

51
Q

How do different NSAIDs differ in their mechanism of action?

A

They have different affinity and efficacy to the COX enzymes

52
Q

What do all NSAIDs act as?

A
  • Anti-inflammatories
  • Analgesics
  • Antipyretics
53
Q

How are NSAIDs administered?

A

Commonly given orally, but can be given topically

54
Q

When are NSAIDs given topically?

A

For local tissue injury

55
Q

What kind of elimination do NSAIDs show?

A

Most show first-order elimination kinetics

56
Q

What are NSAIDs broadly classified into?

A
  • Those with short half lives (<6hrs)
  • Those with long half lives (>10hrs)
57
Q

Give an example of a NSAID with a short half life

58
Q

Give an example of an NSAID with a long half life?

59
Q

Do NSAIDs bind to plasma proteins?

A

Yes, heavily

60
Q

Can NSAIDs act to displace other plasma protein binding drugs?

61
Q

What kinetics does aspirin exhibit?

A

Dose dependant kinetics, whereby at low doses it shows first order, and at high doses shows zero order

62
Q

What is the half life of aspirin at low doses?

63
Q

What results in the main ADRs seen with prostaglandins?

A

Inhibition of COX-1 constitutitive secretion of PG

64
Q

What are the main GI ADRs of NSAIDs?

A
  • Ulceration of stomach
  • Haemorrhage
  • Performation of stomach
65
Q

In whom might NSAIDs cause GI ADRs?

A
  • Long-term users
  • Elderly
66
Q

How do NSAIDs bring about their GI ADRs?

A

PGE2 stimulates mucus production and inhibits acid secretion, thus inhibition of PGE2 production will result in damage directly to the stomach on ingestion and systemically

67
Q

Who is susceptible to renal ADRs of NSAIDs?

A

Compromised HRH individuals

68
Q

What are the renal ADRs of NSAIDs?

A
  • Reduced GFR
  • Reduced perfusion of the kidney
69
Q

How do NSAIDs bring about their renal ADRs?

A

Due to the role PGE2 has in maintaining adequate blood flow

70
Q

What are the vascular ADRs of NSAIDs?

A
  • Increased risk of prolonged bleeding time
  • Increased bruising
  • Increased risk of haemorrhage
71
Q

How do NSAIDs bring about their vascular ADRs?

A

Due to NSAIDs inhibiting thromboxane A2 synthesis, and thus reduced platelet aggregation

72
Q

In what % of individuals do skin rashes occur with NSAID use?

73
Q

Why does particular care need to be taken when prescribing NSAIDs to asthmatics?

A

Asthmatic bronchospasm can sometimes occur

74
Q

What has been done in an attempt to reduce the ADRs seen with NSAIDs?

A

Selective COX-2 inhibitiors have been developed

75
Q

How do selective COX-2 inhibitors reduce the ADRs seen with NSAIDs?

A

Due to theoretical normal COX-1 action

76
Q

What is the problem with selective COX-2 inhibitors?

A

They showed an increased risk of hypertension and cardiac and renal failure, so were never licensed for use

77
Q

What can NSAIDs be used in combination with therapeutically?

A

Low dose opiates

78
Q

What is the advantage of combining the use of NSAIDs with low-dose opiates?

A
  • It extends the therapeutic range for treating pain
  • Reduce the ADRs seen with increased opiate use
79
Q

What happens when you combine multiple NSAIDs?

A

There is an increased risk of ADRs

80
Q

Why is there an increased risk of ADRs when you combine multiple NSAIDs?

A

Because they affect one anothers binding of plasma proteins

81
Q

Where is the interaction between different NSAIDs especially important?

A

In NSAIDs and low dose aspirin administration

82
Q

Why is the interaction between different NSAIDs especially important in NSAIDs and low-dose aspirin administration?

A

As they will compete for the COX-1 binding sites, and interfere with the cardioprotective mechanism of aspirin

83
Q

What is the result of the protein binding of NSAIDs meaning certain drugs are displaced by NSAIDs?

A

May require dose adjustment

84
Q

What drugs have their binding affected by NSAIDs?

A
  • Sulphonylurea
  • Warfarin
  • Methotrexate
85
Q

What needs to be done when administering NSAIDs and sulphonylureas together?

A

You need to decrease the dose of sulphonylureas to prevent hypoglycaemia

86
Q

What needs to be done when administering NSAIDs and warfarin together?

A

You need to decrease the dose of warfarin to prevent increased bleeding

87
Q

What needs to be done when giving NSAIDs and methotrexate together?

A

You need to decrease the dose of methotrexate to prevent a wide range of serious ADRs

88
Q

What is used as the reference NSAID for efficacy and disease severity?

89
Q

How is aspirin unique as an NSAID?

A

It is the only NSAID which irreversibly inhibits COX enzymes via acetylation

90
Q

What is the half life of aspirin?

91
Q

What is aspirin converted to in the body?

A

Salicylate

92
Q

What are the therapeutic uses of aspirin?

A
  • Use as an NSAID
  • Athero-thrombotic disease prevention
  • GI cancer prophylaxis shown in some trials
93
Q

How does aspirin prevent athero-thrombotic disease?

A

By acting as an anti-platelet, as it prevents thromboxane A2 production

94
Q

What GI cancers can aspirin be used as prophylaxis for?

A
  • Colon cancer
  • Possibly upper GI cancers
95
Q

Is paracetamol an NSAID?

A

It is chemically related to NSAIDs, yet has no anti-inflammatory action, and so it is not described as an NSAID but a simple analgesic

96
Q

What is paracetamol effective in?

A

Mild to moderate analgesia and anti-pyrexic

97
Q

What is the advantage of paracetamol over NSAIDs?

A

At therapeutic doses, it has a much better ADR profile than NSAIDs

98
Q

What is the therapeutic dose of paracetamol?

A

8x500mg a day

99
Q

When should the therapeutic dose of paracetamol be changed?

A

In those with compromised hepatic function

100
Q

What is the mechanism of action of paracetamol?

A

Uncertain, yet appears to selectively inhibit COX-activity in the CNS

101
Q

What pharmokinetics does paracetamol display in normal doses?

102
Q

How is paracetamol metabolised?

A
  • 90% enters phase 2 metabolism directly
  • 10% enters phase 1 oxidation to produce NAPQI
103
Q

How is paracetamol metabolised in phase 2 metabolism?

A

60% glucoronidation and 30% sulphonation

104
Q

What is the significance of NAPQI?

A

It is very reactive and toxic

105
Q

Why is NAPQI toxic?

A

As it can act as an oxidiser

106
Q

How is NAPQI detoxified?

A

By phase II conjugation with glutathione

107
Q

What pharmokinetics does the conjugation of NAPQI with gluthathione?

108
Q

What limits the phase II metabolism of NAPQI?

A

The availability of glutathione

109
Q

What happens to the pharmokinetics of paracetamol at high doses?

A

Becomes non-linear for both phase I and phase II metabolism

110
Q

What is the result of the change in pharmokinetics of paracetamol at high doses?

A

Phase II metabolism becomes saturated, and there is a subsequent increase in phase I production of NAPQI.

111
Q

What is the result of the increase of NAPQI that occurs at high doses of paracetamol?

A

It will deplete the glutathione levels until there becomes an increase in unconjugated NAPQI

112
Q

What is the problem with unconjugated NAPQI?

A

It is highly nucleophilic, and binds with cellular macromolecules. There becomes a precipitous loss of hepatic cell function and subsequent hepatic cell death, as well as the potential for causing renal failure.

113
Q

When should the treatment for a paracetamol overdose ideally be performed?

A

Within 8 hours of the overdose

114
Q

What are the potential treatments for paracetamol overdose?

A
  • Oral activated charcoal
  • IV acetylcysteine
  • Oral methionine
115
Q

When is the activated charcoal treatment for paracetamol overdose effective?

A

Within 0-4 hours

116
Q

What effect does activated charcoal have in paracetamol overdose?

A

Can reduce uptake by 50-90%

117
Q

When can IV N-acetylcysteine or oral methionine be given to treat paracetamol overdose?

A

Between 0-36 hours

118
Q

What effect does IV N-acetylcysteine or oral methionine have in paracetamol overdose?

A

Increase gluthathione levels

ESA 5 - Pharmacology NEW (17 decks)

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