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Pharmacology > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

What signals the inflammatory response?

A

Autacoids - diverse range of local molecular mediators and signalling agents

  • bradykinins
  • cytokines
  • nitric oxide
  • histamine
  • leukotrienes
  • neuropeptides
  • eicosanoids
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2
Q

What are features of autacoids? What does this allow?

A

Localised release
Short half-life
Allows fine control of the signalling response

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3
Q

What are eicosanoids derived from?

A

Arachidonic acid

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4
Q

Which class of eicosanoids do prostaglandins belong to? Name another part of the class

A

Prostaglandins

Leukotrienes

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5
Q

Name the types of prostaglandins

A

Prostacyclins

Thromboxanes

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6
Q

List the steps of how prostaglandins are synthesised

A

Cell membrane phospholipids converted to arachidonic acid by phospholipase A2

Arachidonic acid converted to PG’G’ by COX1/2

PG’G’ converted to PG’H’ by COX 1/2

PG’H’ converted to PGs D, E, F, I by specific PG enzymes

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7
Q

Which is the most important prostaglandin for mediating the inflammatory response and what effects does it have?

A

PG ‘E’

  • vasodilation
  • hyperalgesia
  • fever
  • immunomodulation
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8
Q

When is COX 1 expressed and where?

A

All the time - constitutively - has a short half life of around 10 mins
In a wide range of tissue types

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9
Q

What is the role of prostaglandins synthesised by COX-1?

A

Major cytoprotective role in tissues such as

  • gastric mucosa
  • myocardium
  • renal parenchyma

Ensures optimised local perfusion and reduces ischaemia

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10
Q

When and where is COX 2 expressed?

A

Induced by injurious stimuli and inflammatory mediators such as bradykinin
Constitutively expressed in parts of the brain and kidney

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11
Q

Via which COX are the main therapeutic effects of NSAIDs done via?

A

COX 2

COX 1 inhibition by NSAIDs is the reason for ADRs

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12
Q

What is the difference in active sites of COX1 and 2?

A

COX-1 has a narrow ‘mouth’ so can only fit small, sharp, aspirin-like objects
COX-2 has a wide mouth so fit small and big, blunt drugs

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13
Q

What do prostaglandins interact with?

A

Bind with specific GPCRs

-for PG ‘E’, the main receptors are EP1-4

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14
Q

Where are autacoids released from?

A

Blood vessels and local tissues

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15
Q

What do prostaglandins do?

A

Synergise action of other autacoids including bradykinin and histamine
Act as potent vasodilators (do not increase permeability, just synergises effect of the above two)

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16
Q

What do EP1 and EP2 receptors do?

A

EP1 is Gq - increases peripheral nociception

EP2 is Gs - increases vasodilation

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17
Q

What happens when PGE2 is released following trauma/injury?

A

PGE2 binds to EP1 GPCR receptor on C fibre
Activation of this receptor causes
-increased neuronal sensitivity to bradykinin
-inhibition of K+ channels
-increased Na+ channel sensitivity

Acts to increase c fibre activity
Activates previously silent C fibres

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18
Q

How does peripheral sensitisation occur via PGE2?

A

Binds to EP1 which is a Gq GPCR
Leads to an increase in intracellular calcium concentration
Increased neurotransmitter release
Increased sensitivity due to other autacoids

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19
Q

How does central sensitisation to pain occurs?

A

Increased sustained nociceptive signalling peripherally results in increased cytokine levels in the dorsal horn cell body
This increases COX-2 and PGE2 synthesis
PGE2 acts via local GPCR EP2 receptors (Gs)
-increase in cAMP and PKA
-decrease in glycine receptor binding affinity
-increase in sensitivity and discharge rate of secondary interneurones
-increase in pain perception

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20
Q

How does pyrexia occur?

A

Infected/inflammatory states and bacterial endotoxins causes macrophage release of IL-1
In the hypothalamus, IL-1 (possibly by induction of COX-2) stimulates PGE2 synthesis
PGE2 binds with EP3 receptors - Gi type GPCR

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21
Q

What can NSAIDs be used as?

A

Analgesics
Anti-inflammatories
Antipyretics

22
Q

What type of pharmacokinetics do NSAIDs show?

A

Linear

23
Q

What is the half life of NSAIDs?

A

Two groups

  • less than 6 hours
  • more than 10 hours
24
Q

What is protein binding like with NSAIDs?

A

Heavily bound - 90-99%

25
Q

What are some GI ADRs of NSAIDs?

A 
Stomach pain
Nausea
Heart burn
Gastric bleeding
Ulceration
26
Q

How do NSAIDs cause a lot of their GI ADRs?

A

Inhibit gastric COX-1 PGE2

  • decrease in cytoprotective mucus secretion
  • increased acid secretion
  • reduced mucosal blood flow
27
Q

How can GI ADRs be reduced with NSAIDs?

A

PPIs

Misoprostol (a synthetic of PGE)

28
Q

How do NSAIDs cause renal ADRs?

A

More common in neonates and elderly due to reduced renal perfusion blood flow

  • PGE2 and PGI2 are inhibited, leading to less dilation of afferent arteriole
  • Na/K/Cl and H2O retention occurs due to decreased GFR, so increased likelihood of hypertension
29
Q

What are some vascular ADRs?

A

Increased risk of bleeding time, bruising and haemorrhage

30
Q

Why are some hypersensitivity ADRs with NSAIDs?

A

Skin rash
Stevens-Johnson syndrome - rare but serious - rash of skin and mucous membranes and can compromise hepatic function

Can affect bronchial asthma, care in asthmatics

31
Q

What is a paediatric ADR that can happen with NSAIDs?

A

Reye’s syndrome - serious brain/liver injury

-don’t give aspirin to children

32
Q

Name some COX-2 inhibitors

A

Rofecoxib

Celecoxib

33
Q

What is the theoretical benefit of specific COX-2 inhibitors?

A

Overcome ADRs due to lack COX-1 inhibition with equal efficacy to standard NSAIDs

34
Q

What are some problems with COX-2 specific inhibitors?

A

Not completely free of GI ADRs
Increased risk of CVS ADRs with long term use
-only approved for short term

35
Q

What is the benefit of combining NSAIDs with low dose opioids?

A

Can extend their therapeutic range for treating pain as they act by different mechanisms
Reduce ADRs seen with opioids when opioids are used by themselves

36
Q

How can combining NSAIDs increase risk of ADRs?

A

Can affect eachother’s PK/PDs due to competition for plasma protein binding sites

NSAIDs and low-dose aspirin compete for COX-1 binding sites, which may interfere with the cardio-protective action of aspirin

37
Q

What are some DDIs of NSAIDs?

A

Affect highly protein-bound drugs such as

  • sulphonylurea - increases to cause hypoglycaemia
  • warfarin - increases to cause increased bleeding
  • methotrexate - increases to cause many ADRs
38
Q

What is different about aspirin compared to other NSAIDs?

A

It is the only NSAIDs to irreversibly inhibit COX enzymes by acetylation

39
Q

Why does aspirin have a unique PK profile?

A

Half-life is less than 30 minutes

Rapidly hydrolyse in the plasma to salicylate

40
Q

What order kinetics does salicylate have?

A 
Lower doses - linear, half-life is four hours
Higher doses (12x300mg aspirin/day) - zero order kinetics
41
Q

What are the current and possible uses of aspirin?

A

Cardioprotective (75mg/day)
Reduces platelet aggregation

Prophylactic for GI, breast and other cancers

42
Q

How does aspirin reduce platelet aggregation?

A

Irreversibly inhibits COX-1 activity that normally drives pro-aggregate activity in both platelets and the vessel wall

-reduces the likelihood of thrombotic formation

43
Q

How is aspirin thought to prevent against tumour growth?

A

Cancers synthesise PGE2 which promotes tumour growth

44
Q

What is paracetamol used for?

A

Mild-moderate analgesia and fever

45
Q

Why is paracetamol better than NSAIDs?

A

Better ADR profile

46
Q

How is paracetamol thought to work?

A

Weak COX1/2 inhibitor
Primarily acts on CNS, possibly on COX-3 isoform
Metabolite in CNS may combine with arachidonic acid to block binding with COX-1/2

47
Q

Order of pharmacokinetics of paracetamol?

A

First order

High dose - zero order

48
Q

Half-life of paracetamol?

A

2-4 hours

49
Q

Who do you need to be careful prescribing paracetamol for?

A

Those with compromised hepatic function or alcoholics

50
Q

What is the normal metabolism of paracetamol?

A

Phase II conjugation with glucuronide (60%) and sulphate (30%) via CYP450 enzymes

Some phase I oxidation to produce NAPQI (reactive and toxic). Detoxified and conjugated with glutathione

51
Q

How is NAPQI so toxic?

A

Highly reactive and nucleophilic
Binds with cellular macromolecules and mitochondria
Leads to loss of function and hepatic cell death
Can cause renal failure

52
Q

How is paracetamol overdose treated?

A

Within 4 hours - give activated charcoal to reduce uptake

0-36 hours - start IV N-acetylcysteine

Give methionine PO if NAC cannot be given promptly

Pharmacology (23 decks)

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