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Clinical Pharmacology & Intro to Prescribing > Session 8: NSAIDs > Flashcards

Session 8: NSAIDs Flashcards

1
Q

Briefly explain the production of prostanoids.

A

Arachidonic acid from phospholipids.

The arachidonic acid will then be converted into PGE2, PGF2, PGD2, PGI2 or TXA2 depending on whether it is converted with enzyme COX-1 or COX-2.

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2
Q

What else can be arachidonic acid be converted into?

A

Leukotrienes via lipooxygenase pathways.

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3
Q

Give examples of prostanoids.

A

Prostaglandins

Prostacyclin

Thromboxanes

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4
Q

Where are prostanoids produced?

A

Locally on demand

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5
Q

What is the therapeutic benefit of prescribing NSAIDs?

A

A result of inhibiting down stream products of arachidonic acid.

Also many of the ADRs stem from the inhibition of this pathway.

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6
Q

What are arachidonic acid derived primarily from?

A

Dietary linoleic acid like vegetable oils.

They are then converted hepatically to arachidonic acid and incorporated into phospholipids.

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7
Q

Where can arachidonic acid be found?

A

Throughout the body

Particularly in muscle, brain and liver.

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8
Q

Functions of PGE2.

A

GI mucosal protection

Uterine contraction

Brain

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9
Q

Functions of PGF2.

A

Bronchoconstrictor

Uterine contraction

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10
Q

PGD2 functions

A

Bronchoconstrictor

Inhibits platelet aggregation

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11
Q

Functions of PGI2 (prostacyclin)

A

Inhibits platelet aggregation

Vasodilator

Endothelium

Kidney

Brain

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12
Q

Functions of thromboxane A2

A

Platelet aggregator

Vasoconstrictor

Macrophages

Kidney

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13
Q

General functions of PGE2, PGF2 and PGD2.

A

Cause pain, pyrexia and inflammation.

PGE2 is generally good for the stomach as well.

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14
Q

Prostacyclin and CVS

A

Cytoprotective of the CVS

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15
Q

Thromboxane A2 and CV

A

Generally bad for the CVS

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16
Q

What are the two functional isoforms of COX.

A

COX-1

COX-2

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17
Q

COX-1 activity

A

Constitutively active across most tissues.

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18
Q

COX-2 activity.

A

Inducible.

However constitutively active in chronic inflammation in brain, kidney and bone.

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19
Q

Homeostatic functions COX-1.

A

GI protection

Platelet aggregation

Vascular resistance

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20
Q

Homeostatic functions of COX-2.

A

Renal homeostasis

Tissue repair and healing

Reproduction

Inhibition of platelet aggregation

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21
Q

Pathological functions of COX-1.

A

Chronic inflammation

Chronic pain

Raised BP

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22
Q

Pathological functions of COX-2.

A

Chronic inflammation

Chronic pain

Fever

Blood vessel permeability

Tumour cell growth

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23
Q

What receptor type do prostanoids act on?

A

GPCRs

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24
Q

What is prostanoid action often enhanced by?

A

Local autacoids such as bradykinin and histamine.

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25
Q

What is the relationship between TXA2 and PGI2? (other than both being prostanoids)

A

They have opposing vascular effects.

This means that there is a fine balance between them that is crucial.

Haemodynamic vs thrombogenic control

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26
Q

Complications of imbalance between TXA2 and PGI2.

A

Hypertension

MI

Stroke

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27
Q

Fish oil and TXA2/PGI2.

A

TXA2 and PGI2 can be converted to TXA3 and PGI3 in a rich fish oil diet.

TXA3 and PGI3 are better prostanoids

28
Q

General use of NSAIDs.

A

Analgesic and anti-inflammatory effects

29
Q

How does the efficacy of NSAIDs relate with inflammation?

A

Greater efficacy when inflamed.

30
Q

Explain the mechanism behind NSAIDs analgesic effect.

A

Inhibition of PGE2 reduces peripheral pain fibre sensitivity.

Less PGE2 synthesis in the dorsal horn leads to less neurotransmitter release.

Less NT leads to lower excitability of neurons in pain relay pathway.

31
Q

Explain the effects of NSAIDs in terms of initial dosing.

A

Efficacious after first dose but full analgesia after several days dosing.

32
Q

What happens if COX activity increases?

A

Prostaglandin increases and vasodilation and oedema does as well.

33
Q

How do NSAIDs relieve oedema?

A

Vasodilation in post capillary venules contributes to increased permeability and local swelling of tissue leading to oedema.

NSAIDs will inhibit it.

34
Q

Explain an important function of PGE2.

A

A critical component in the preoptic area of the hypothalamus which is the thermoregulatory centre.

35
Q

Explain NSAIDs’ role as antipyretics.

A

Pyrogens like IL-1 and IL-6 stimulate conversion of arachidonic acid into prostaglandins by hypothalamic COX-2.

This will act on the thermoregulatory centre to elevate the set point of internal temperature leading to the person becoming febrile.

36
Q

How are NSAIDs differentiated?

A

By their selectivity to COX-1 or COX-2.

37
Q

Why have a lot of NSAIDs moved over to a COX-2 selectivity?

A

Because there is a high prevalence of ADRs attributable to COX-1 inhibition.

38
Q

NSAIDs action on leukotrienes.

A

No direct action on leukotrienes as they do not use COX in the lipooxygenase pathway.

However there is an indirect action via PGE2.

39
Q

Give examples of NSAIDs.

(Need to know all)

A

Aspirin

Ibuprofen

Naproxen

Diclofenac

Celecoxib

Etoricoxib

40
Q

Most common ADR of NSAIDs.

A

GI such as dyspepsia, nausea, peptic ulceration, bleeding and perforation.

The relative risk of GI bleed depends on the NSAID and its selectivity.

41
Q

Explain why NSAIDs can cause GI ADRs.

A

Reduction of mucus and bicarbonate secretion.

Increased acid secretion (prostaglandin inhibits H+ secretion)

Reduction in mucosal blood flow as reduction in prostaglandin leads to less vasodilation. This leads to enhanced cytotoxicity and hypoxia.

Also causes local irration and bleeding from rectum.

42
Q

NSAIDs and IBD.

A

NSAIDs can exacerbate IBD

43
Q

Give example of when to use NSAIDs with caution due to their GI ADRs.

A

Elderly

Prolonged use

When on glucocorticoid steroids

Anticoagulants

Smoking

Alcohol

History of peptic ulceration

H. pylori

44
Q

Explain renal ADRs due to NSAIDs.

A

Prostaglandins such as PGE2 and PGI2 (Prostacyclin) usually cause vasodilation of the afferent arteriole of the glomerulus.

In the case of NSAIDs the vasodilation will be less which can lead to reduced GFR and reduced renal blood flow.

This is usually not a problem at therapeutic dose in healthy people.

45
Q

Which people are at greater risk of renal ADRs?

A

In underlying CKD or heart failure.

Very young and elderly are generally at risk.

46
Q

Explain prostaglandins action in the collecting duct.

A

Inhibits sodium absorption leading to natriuresis.

If you give NSAIDs this action will be inhibited and can lead to increased sodium, more water and therefore higher blood pressure.

47
Q

Give exampels of selective COX-2 inhibitors.

A

Celecoxib

Etoricoxib

48
Q

Advantages of COX-2 inhibitors.

A

Less GI ADRs

The renal ADRs stay similar to non-selective.

They do not share the same antiplatelet action as non-selective but they do inhibit PGI2 from leading to unopposed aggregatory effects.

They can also be useful when monitored in severe OA and RA

49
Q

Explain NSAIDs interaction with protein binding.

A

NSAIDs will displace other bound drugs leading to the other drug becoming more free in the blood and therefore more active.

This can give ADRs of the drug that has been displaced by NSAIDs.

Dose adjustment will be needed.

50
Q

Give examples of drugs that are displaced by NSAIDs and should therefore be used with caution in combination.

A

Sulfonylurea will be displaced which can lead to hypoglycaemia.

Methotrexate will be displaced which can lead to hepatotoxicity, leukopenia and RA

Warfarin will be displaced and lead to increased risk of bleeding

51
Q

Contraindications of NSAID use.

A

Should not be used in CVS disease

Renal disease

GI disease

Need to be cautious when patient is on ACEi, ARBs, Diuretics, sulfonylureas, methotrexate, warfarin.

52
Q

Give examples of when NSAIDs should be used.

A

Inflammatory conditions

OA (topical first)

Postoperative pain

Topical use on cornea

Menorrhagia

Low dose aspirin as blood thinner

Opioid sparing.

53
Q

Paracetamol vs NSAIDs.

A

Non-NSAID for mild to moderate analgesia and fever.

Paracetamol have fewer common ADRs, no effect on platelets and limited ADRs on GI.

It has a very little anti-inflammatory action.

54
Q

Briefly explain mechanism of paracetamol.

A

Not entirely known but seems to be COX-2 selective inhibition in the CNS.

55
Q

What is NAPQI?

A

A highly reactive metabolite of paracetamol which can be harmful in excessive amounts.

56
Q

Why is NAPQI usually not a problem?

A

Because at normal therapeutic doses there is conjugation of NAPQI with glutathione which renders the NAPQI harmless.

However hepatic glutathione is limited.

57
Q

Explain NAPQIs toxic effect.

A

Highly nucleophilic and will oxidise key metabolic enzymes.

This will ultimately lead to cell death via necrosis and apoptosis.

58
Q

How much of a dose of paracetaml is needed to cause irreversible damage?

A

150mg/kg

59
Q

Pattern of symptoms in paracetamol overdose.

A

Can be asymptomatic for many hours and then get nauseous, start vomiting and get abdo pain during the first 24h.

Maximal liver damage will arise around 3-4 days

60
Q

When should bloods be taken and what are issues with taking blood?

A

Not before 4 hours.

This is done to check the extent of the overdose but can be problematic as the patient may have taken bolus doses in intervals and not just all at ones.

61
Q

What can be given as treatment of paracetamol overdose?

A

Activated charcoal

N-acetylcysteine

62
Q

What are issues with activated charcoal?

A

Only good if we know the exact time of when overdose was taken and if it is only taken all at once.

We rarely know this and issues arise if there were interval bolus doses or a gradual increase in consumption over time.

63
Q

Explain action of N-acetylcysteine.

A

Replenishes glutathione thiol and replaces it to conjugate NAPQI and render it harmless.

64
Q

Why is not glutathione given?

A

Because it won’t be taken up and reach the hepatocytes.

65
Q

Explain the difference in action of COX-1 inhibition vs COX-2 inhibition in relation to platelet aggregation.

A

COX-1 inhibition leads to inhibition of platelet aggregation as COX-1 usually promotes platelet aggregations (via TXA2).

COX-2 inhibition leads to platelet aggregation as COX-2 usually promotes inhibition of platelet aggregation via PGI2.

66
Q

Which of the NSAIDs discussed is most selective for COX-2?

A

Etoricoxib

67
Q
A

Clinical Pharmacology & Intro to Prescribing (24 decks)

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