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Clinical Pharmacology and Therapeutics > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

What are the 3 primary therapeutic effects of NSAIDs?

A

Analgesia
Anti-inflammatory
Antipyretic

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2
Q

What is the key action of NSAIDs?

A

Prostaglandin synthesis enzyme inhibition

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3
Q

What are autacoids?

A

A diverse range of local molecular mediators and signalling agents

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4
Q

Give some examples of autocoids.

A 
Bradykinins
Histamine
Cytokines
Leukotrienes
Nitric oxide
Neuropeptides
Prostaglandins
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5
Q

When are autocoids released?

A

In response to local injury to tigger a local response

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6
Q

What are prostaglandins synthesised from?

A

Arachidonic acid

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7
Q

What enzymes are used in prostaglandin synthesis?

A

COX Enzymes (Cyclo-oxygenase)

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8
Q

Describe the pathway of prostaglandin synthesis.

A

Cell membrane phospholipids -> arachidonic acid (Phospholipase A2)
Arachidonic acid -> PG “G” (COX-1/COX-2)
PG “G” -> PG “H” (COX-1/COX-2)

PG “H” to D, E, F, and I via further specific enzymes

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9
Q

Which PG is the most important in mediating the inflammatory response?

A

E

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10
Q

What effects for PGs have, especially E?

A

Vasodilation
Hyperalgesia
Fever
Immunomodulation

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11
Q

Where is COX-1 expressed?

A

Throughout a wide range of tissues

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12
Q

Where and for what is PG synthesis by COX-1 very important?

A

Cytoprotective role in the:

  • Stomach mucosa
  • Myocardium
  • Renal parenchyma
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13
Q

What is the half life of PG?

A

Short, so need constant synthesis

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14
Q

What are most NSAID ADRs caused by?

A

The effect of NSAIDs on COX-1

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15
Q

Where is COX-2 expressed?

A

Induced by injury and inflammatory mediators such as bradykinin.
Also in part of the brain and kidney constitutively.

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16
Q

Via which of the COX enzymes do NSAIDs exert their main therapeutic effect?

A

COX-2

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17
Q

Do COX 1 and 2 work independantly or together?

A

Independantly

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18
Q

Why do different NSAIDs work differently on COX 1 and 2?

A

COX-1 and 2 have different tunnel for catalysing arachidonic acid, so different shaped drugs fit the different enzymes.

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19
Q

What kind of receptor do PGs have?

A

GPCRs

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20
Q

How do PGs act on blood vessels?

A

As potent vasodilators

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21
Q

Which PG receptor increases afferent nociception?

A

EP-1

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22
Q

Which PG receptor causes vasodilation?

A

EP-2

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23
Q

What happens when a PG binds to its receptor?

A

GPCR is activated -> increased neuronal sensitivity to bradykinin, K+ channel inhibition, and increased sensitivit of Na2+ channels.

This all causes increased C fibre activity, including previously silent C fibres.

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24
Q

How is pyrexia caused by PGs?

A

Infection/inflammation -> IL-1 release from macrophages which stimulates PGE2 synthesis in the hypothalamus. PGE2 acts on EP3 receptor which causes heat production and decreased heat loss.

25
Q

How do NSAIDs generally inhibit COX1 and 2?

A

As competative inhibitors - occupy the hydrophobic channel

26
Q

How many NSAIDs are there roughly?

A

50

27
Q

Tell me about the pharmacokinetics of NSAIDs.

A

Can be given orally (typical) but also topically for soft tissue injury.
Linear pharmacokinetics
2 groups of half lives - under 6 hours, or over 10 hours.
90-99% bound to plasma proteins.

28
Q

When are NSAIDs used?

A

In inflammatory disorders such as RA or OA

Analgesia for mild to moderate pain

29
Q

NSAIDs vs Opioids

A

NSAIDs are less effective but have a better ADR profile

30
Q

What are the ADRs associated with NSAIDs?

A

Many many…
Stomach and GI tract major side effects
Renal ADRs in pts with Heart, hepatic, or renal impairment, or hypovolaemia.

31
Q

What GI side effects can NSAIDs have?

A

Varying degrees of stomach pain, nausea, heart burn, gastric bleeding, ulceration.

32
Q

How can we offset some of the GI ADRs of NSAIDs?

A

Give a PPI alongside, or misoprostol if using long term

33
Q

What % of pts on NSAIDs get GI side effects?

A

35%, and some may be asymptomatic

34
Q

What renal/renovascular ADRs can pt on NSAIDs get?

A

Decreased renal perfusion -> decreased eGFR, Na2+, K+, Cl- and water retention -> hypertension.

35
Q

Which renal vascular element do NSAIDs act on and how?

A

Prevent vasodilation of the afferent arterioles by inhibiting COX-1/2 so PG synthesis prevented.

36
Q

Can people be allergic to NSAIDs?

A

Some people can have a hypersensitivity rxn to NSAIDs. Some NSAIDs have skin rash rate of 15%, usually mild. Can get Steven Johnson syndrome (vvv rare).

37
Q

What is Steven Johnson syndrome?

A

Immune complex mediated hypersensitivity rxn, with compromised hepatic function, and rash of skin and mucous membranes.

38
Q

What can happen to children who take NSAIDs?

A

They can have paediatric Reyes syndrome - rare serious brain/liver injury, usually comes about due to viral infection treated with aspirin.

39
Q

What have clinical trials shown to be the problem of specific COX-2 inhibitors?

A

Long term use leads to increased risk of CVS ADRs

40
Q

What can NSAIDs be used alongside?

A

Low dose opiates to extend therapeutic range and reduce opiate ADR profile.

41
Q

What can happen between NSAIDs and aspirin?

A

NSAIDs can interfere with aspirins cardioprotective action, and compete for plasma protein binding sites.

42
Q

What drugs require dose adjustments when taken with NSAIDs, and why?

A

Sulphonylurea
Warfrain
Methotrexate

Competative displacement by NSAIDs, so have to avoid PK and PD changes.

43
Q

What is the risk of NSAID + sulphonylurea?

A

Increases BA of sulphonylurea -> hypoglycaemia

44
Q

What is the risk of NSAID + warfarin?

A

Increases warfarin BA -> bleeding

45
Q

What is the risk of NSAID + methotrexate?

A

Wide range of ADRs associated with methotrexate

46
Q

How does aspirin work?

A

Irreversibly inhibits COX enzymes by acetylation. Unique in its MoA.

47
Q

What is unusual about aspirins pharmacokinetics?

A

T1/2 is less than 30 minutes.
Hydrolysed in plasma to salicylate.
First order kinestics at lower doses. Zero order at higher doses.

48
Q

What is paracetamol?

A

A unique non-NSAID non-opiate analgesic

49
Q

What actions does paracetamol have?

A

Virtually no anti-inflammatory action.

Mild/moderate analgesic and antipyrexic

50
Q

What kind of therapeutic index does paracetamol have?

A

A low one - even 10 tablets in an hour is potentially fatal.

51
Q

What is the MoA of paracetamol?

A

Weak COX-1 and 2 inhibitor, with potential action on CNS COX-3 isoform (unable to isolate yet).
Also metabolite combines with arachidonic acid to block bidning of COX-1 and 2 in the CNS.

52
Q

What is the t1/2 in healthy patients for paracetamol?

A

2-4 hours

53
Q

Who needs to careful around paracetamol?

A

Pts with impaired hepatic function or alcoholics

54
Q

How is NAPQI toxic?

A

V reactive - binds to cellular macromolecules and mitochondria -> loss of function -> necrotic hepatocyte death.

55
Q

When is the peak for hepatotoxic effects of a paracetamol overdose?

A

72-96 hours post ingestion

56
Q

How much can activated charcoal reduce paracetamol uptake by?

A

50-90% if given within an hour of ingestion

57
Q

What is the management of paracetamol overdose?

A

IV N-acetylcysteine according to blood levels of paracetamol 4 hours post ingestion.

Psychiatric assessment, and supportive treatment.

58
Q

What can we give if N-acetlycysteine can’t be given promptly for a paracetamol overdose?

A

Methionine

Clinical Pharmacology and Therapeutics (26 decks)

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