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Case 1 > Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol > Flashcards

Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol Flashcards

1
Q

What cleaves fatty acids from the membrane phospholipids

A

PLA2

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2
Q

What does PLA2 generate

A

Arachidonic acid (AA)

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3
Q

What is AA

A

A polyunsaturated (many double bonds) omega-6 fatty acid. It is the most widely used fatty acid precursor of all bioactive lipids

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4
Q

What makes AA a versatile lipid precursor

A

The number and position of double bonds. The double bonds ‘kink’ the molecule

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5
Q

What do lipoxygenase do

A

Convert AA into eicosanoids

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6
Q

What eicosanoids further modified to

A

Leukotrienes

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7
Q

What do leukotrienes have roles in

A

Chemotaxis, bronchoconstriction and vascular permeability

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8
Q

What are leukotrienes role in bronchoconstriction

A

They are involved in the inflammatory response

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9
Q

What is PGHS

A

Prostaglandin-H synthase

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10
Q

What do PGHS enzymes do

A

Convert AA into endoperoxides (PGG2 and PGH2) which can then be modified into cell-specific prostanoids

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11
Q

What is the PGHS enzyme comprised of

A

1 unit with 2 catalytic domains: COX domain and and peroxidase domain

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12
Q

What does the COX domain of the PGHS enzyme do

A

AA and O2 enter the COX domain togetehr and are converted into PGG2

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13
Q

What does the peroxidase domain of the PGHS enzyme do

A

PGG2 is converted to PGH2

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14
Q

What are the 3 isoforms of PGHS

A

PGHS-1, PGHS-2 and PGHS-3

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15
Q

What are the physiological (good) effects of PGHS-1

A

GI tract, platelet, vascular and CNS function

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16
Q

What are the pathophysiological (bad) effects of PGHS-1

A

Chronic pain, hypertension

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17
Q

What the the physiological (good) effects of PGHS-2

A

Renal, platelet, vascular, reproductive and CNS function

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18
Q

What are the pathophysiological (bad) effects of PGHS-2

A

Inflammation, chronic pain, fever, vascular permeability, angiogenesis, tumour growth and neurodegeneration

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19
Q

What can prostaglandins be converted into

A

PGE2, PGF2, TXA2 and PGI2

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20
Q

What converts prostaglandins

A

Cell specific prostaglandin synthases/ isomerases

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21
Q

What are the functions of PGE2

A

Pathophysiology in GI mucosa and renal function, uterine contraction, vasodilation, histamine, bradykinin, eosinophil and basophil chemotaxis

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22
Q

What are the functions of PGF2

A

Bronchoconstrictor, uterine contractor

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23
Q

What are the functions of PGD2

A

Bronchoconstrictor, anti-platelet aggregation

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24
Q

What are the functions of TXA2

A

Platelet aggregation, vasconstrictor

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25
Q

What are the functions of PGI2

A

Physiology in anti-platelet aggregation, vasodilation, endothelial and CNS function

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26
Q

What are prostaglandin receptors on target cell membranes called

A

Prostanoid receptors which are all GPCRs (G-protein coupled receptors)

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27
Q

What implications does the fact that the receptors are GPCRs mean

A

The receptors have paradoxical (opposite to what you expect) effects as the effect that takes place depends on which G protein subtype is activated

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28
Q

What is the class of action of all NSAIDs

A

They inhibit COX domain activity in PGHS preventing the generation of endoperoxides PGG2 and PGH2 by preventing the catalytic cycle and stopping the ability to produce PGH2 and downstream prostaglandins

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29
Q

What are the therapeutic uses of NSAID inhibition of PGHS-2 (e.g. PGE2) derived prostaglandins

A

Reduces the extent and duration of local inflammation caused by vasodilation and increased vascular permeability

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30
Q

When prescribing NSAIDs what do you, as a doctor, need to balance

A

The inflammation response occurring and the response going beyond normal and therefore the need to moderate with NSAIDs

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31
Q

What are NSAIDs not as strong as

A

Steroids in anti-inflammatory drugs

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32
Q

What are analgesic effects

A

Decrease in pain and swelling

33
Q

What are anti-pyretic effects

A

Decrease in temperature

34
Q

What two main effects do NSAIDs have

A

Analgesic and anti-pyretic

35
Q

How do NSAID have analgesic and anti-pyretic effects

A

They inhibit PGH2 production

36
Q

What does PGH2 do

A

PGH2 supercharges the pain response: PGHS-1 derived from PGE2 normally sensitises Aδ and C nociceptive neurons to serotonin, bradykinin and substance P

37
Q

What effect does NSAIDs inhibiting hypothalamic PGHS-2 have

A

PGHS-2 normally generated PGE2 in response to circulating pyrogens, so by clocking PGE2 you stop pyrexia

38
Q

What is pyrexia

A

Fever

39
Q

What are pyrogens and give an example

A

Something that increases temperature such as PGE2

40
Q

What is the chemical name for aspirin

A

Acetyl salicylic acid

41
Q

What is aspirin the only NSAID to do

A

Irreversibly inhibit PGHS-1 and PGHS-2

42
Q

What is the method of action of aspirin

A

Acetylation of serine residue in the COX domain active site

43
Q

What is the origin of aspirin

A

Willow tree bark (containing salicin) was known to reduce pain, fever and inflammation since the time of Hippocrates. Chemists at Bayer derived salcin to the more gastrically tolerable ASA

44
Q

What is the benefit of using aspirin in most MI pateints

A

It helps prevent another myocardial infarction because it can reduce the risks of occlusive vascular events by inhibiting platelet aggregation

45
Q

How is ibuprofen produced

A

As a racemate which means that a racemic mixture is produced

46
Q

What is a racemic mixture

A

A mixture that has stereoisomers

47
Q

Describe the racemic mixture of ibuprofen

A

The S-enantiomer (left) is the active NSAID, the righ enantiomer has no effect in the body

48
Q

What is the method of action of ibuprofen

A

It competes with AA for the COX domain active site of PGHS-1 and PGHS-2. It is a reversible, competitive inhibitor.

49
Q

What is the origin of ibuprofen

A

It is derived from propanoic acid and synthesised by chemists working in boots in the 1960s

50
Q

What is a new use for ibuprofen that is different from its primary intended use

A

Some research data indicates that it may be beneficial in preventing/ retarding Parkinson’s disease

51
Q

What is Rofecoxib

A

A selective inhibitor of PGHS-2

52
Q

What was Rofecoxib used for

A

Prescribed for oesteoarthritis symptoms for which is was very effective

53
Q

Why do we not selectively target PGE2 receptors

A

PGHS-2 has significant but subtle cardiovascular effect, data showed those who took high-dosage Rofecoxib had an increased risk of heart attack and stroke

54
Q

According to the BNF was are the two most important adverse drug reactions associated with NSAID use

A

Potential for gastric ulceration and compromised renal function

55
Q

How do NSAIDs cause gastric ulceration

A

NSAIDs can damage the gastroduodenal mucosa via several mechanisms:

56
Q

Via which mechanisms do NSAIDs damage the gastroduodenal mucosa

A

topical irritant effect of these drugs on the epithelium, impairment of the barrier properties of the mucosa, suppression of gastric prostaglandin synthesis, reduction of gastric mucosal blood flow and interference with the repair of superficial injury

57
Q

How do NSAIDs compromise renal function

A

Inhibition of PGE2 synthesis can lead to increased sodium reabsorption, causing peripheral oedema

58
Q

What is another electrolyte disturbance that can occur as a result of prostaglandin synthesis in the kidney

A

Hypercalcemia, the risk may be particularly high in patients receiving potassium supplementation, potassium-sparing diuretics or ACE inhibitors

59
Q

What risk factors predispose patients to NSAID-sodium retention and oedema

A

Diabetes mellitus, renal disease, circulatory compromise and age

60
Q

What are the effects of NSAIDs on electrolyte and water homeostasis seem to depend upon

A

Dose (dose-dependent)

61
Q

When are NSAIDs contra-indicated

A

If pregnant, sensitised to salicytes/ NSAID allergic, already on an NSAID, do not use ASA if younger than 16 years old

62
Q

Why should patients under the age of 16 not be given aspirin

A

There is an association with the development of Reye’s Syndrome

63
Q

What does Reye’s syndrome have potentially fatal effects in

A

The brain and the liver

64
Q

What are the signs and symptoms of Reye’s stage I

A

Rash on palms and feet, heavy vomitting, lethargy, confusion, nightmares, pyrexial and headaches

65
Q

What are the signs and symptoms of Reye’s stage II

A

encephalitis-induced stupor, hyperventilation, fatty liver (steatosis), hyperactive reflexes

66
Q

What are the signs and symptoms of Reye’s stage III

A

More of stage I and stage II symptoms, potential for coma, potential for cerebral oedema, occasionally respiratory arrest

67
Q

What are the signs and symptoms of Reye’s stage IV

A

Deepening coma, mydriasis (dilation of the pupil) with minimal response to light, hepatic dysfunction

68
Q

What are the signs and symptoms of Reye’s stage V

A

Rapid onset of following stage IV: deep coma, seizures, systemic organ failure, flaccidity, hyperammonemia, death

69
Q

Why is paracetamol your first choice for low levels of pain

A

It is better tolerated from a gastro point of view than ibuprofen

70
Q

Why may paracetamol be chosen over NSAIDs

A

It can have better analgesic (pain) and anti-pyretic (reducing temperature) effects

71
Q

What does paracetamol have very little of

A

Anti-inflammatory activity

72
Q

What is the method of action of paracetamol

A

Under debate: may affect peroxidase domain activity in PGHS-2 or PGHS-3 in the CNS or its metabolites may be having affects in the CNS

73
Q

How are the guildines for pain management organised

A

As a WHO pain ‘ladder’, it was constructed with managing cancer pain in mind

74
Q

What is the organisation of the WHO pain ladder and associated reccomended drugs

A

Mild pain (paracetamol and/or NSAIDs) -> moderate pain (paracetamol and weak opioid e.g. codeine phosphate) -> severe pain (strong opioid e.g. morphine or heroin). If neuropathic in severe pain may consider tri-cyclic anti-depressants and/or Na+ channel blockers

75
Q

Describe opioids

A

They are very good at relieving pain, however they are associated with addiction

76
Q

Give one example of when can heroin be prescibed

A

To help deal with the pain associated with childbirth

77
Q

What do PGHS enxymes generate

A

endoperoxidase precursors for all the prostanoids

78
Q

What do NSAIDs inhibit and how

A

They inhibit PGHS enzymes, typically by blocking cyclo-oxygenase domain activity

79
Q

What best described the mechanism of action of aspirin

A

It causes irreversible inhibition of the cyclo-oxygenase domain of PGHS by acetylation of the key serine residue

Case 1 (10 decks)

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