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ESA 4- Clinical Pharmacology > 8. NSAIDs > Flashcards

8. NSAIDs Flashcards

1
Q

Name examples of chemical signals mediating inflammation.

A

Autacoids (localised release and short 1/2 lives - allows fine control):

  • bradykinin
  • histamine
  • cytokines
  • leukotrienes
  • nitric oxide
  • eicosanoids, inc. prostaglandins
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2
Q

Describe the prostaglandin synthesis pathway.

A

i. Cell membrane phospholipids are cleaved to arachidonic acid by phospholipase A2…
ii. arachidonic acid is converted to PG ‘G’ and then PG ‘H’ by COX-1/-2…
iii. PG ‘H’ then converted to other PGs (D, E, F and I), prostacyclins and thromboxanes.

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3
Q

Which is the most important PG in the inflammatory response and name 4 of its effects?

A

PG E:

  • vasodilation
  • hyperalgesia (increased sensitivity to pain)
  • pyrexia
  • immunomodulation
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4
Q

What are the different roles of the COX-1 and COX-2 isoforms and their PG products?

A

COX-1

  • constitutively expressed throughout body - short PG 1/2 time (10 mins)
  • ‘tight’ active site
  • synthesises PGs with major cytoprotective roles: protective gastric mucous secretion, gastric acid regulation, platelet aggregation, maintenance of renal blood flow, optimises local perfusion (reduces ischaemia)

COX-2

  • expression induced by inflammatory mediators, e.g. bradykinin
  • ‘baggy’ active site
  • synthesises PGs involved in inflammation, pain and fever
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5
Q

How do the effects of PG E synergise with those of other autacoids?

A

PG E released from local tissues and BVs binds with 4 main types of GPCRs: EP 1-4…

  1. EP1 R Gq (pain fibre) - increased peripheral nociception
  2. EP2 R Gs (blood vessel) - increased vasodilation

Don’t increase capillary permeability directly but synergise with permeating effects of bradykinin/histamine.

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6
Q

Describe how PG E sensitises peripheral nociception.

A

i. PG E2 binds to EP1 (Gq GPCR) on peripheral afferent C-fibres…
ii. increases neuronal sensitivity to bradykinin, inhibits K+ channels (prevents hyperpolarisation thus closer to threshold) and increases Na+ channel sensitivity (easier to fire AP)…
iii. increases intracellular Ca2+ and thus NT release…
iv. increased C-fibre activity.

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7
Q

Explain how sustained peripheral nociception sensitises central nociception.

A

i. Sustained increased in peripheral nociceptive signalling…
ii. increased cytokine levels in dorsal horn cell body…
iii. increased COX-2 synthesis and thus PG E2 synthesis…
iv. PG E2 binds to EP2 Rs (G2 GPCRs) on dorsal horn…
v. increases cAMP and PKA…
vi. decreases glycine R binding affinity - removal of glycynergic inhibition…
vii. increases sensitivity and discharge rate of secondary interneurones…
viii. increases CNS pain perception.

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8
Q

Explain how bacterial endotoxins stimulate pyrexia.

A

i. Bacterial endotoxins stimulate macrophage release of IL-1 within hypothalamus…
ii. increases PG E2 synthesis (via COX-2 induction?)…
iii. binds to EP3 (Gi GPCR) in brain…
iv. increased heat production and decreased heat loss

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9
Q

What is the difference between allodynia, hyperalgesia and spontaneous pain?

A 
Allodynia = pain evoked by a normally non-painful stimulus (i.e. central pain sensitisation)
Hyperalgesia = increased sensitivity to pain (mediated by PGs) in response to an injurious stimulus.

Spontaneous pain = pain felt when there is no stimulus, indicating increased C-fibre discharge rate.

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10
Q

Which enzyme do NSAIDs inhibit to produce their effects?

A
  • therapeutic effects via COX-2 inhibition

- ADRs due to COX-1 inhibition (so loss of protective PG effects)

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11
Q

Name the 3 main therapeutic effects of NSAIDs. For which conditions can they be used?

A
  1. anti-inflammatory… used in MSK disorders, e.g. rheumatoid/osteoarthritis
  2. pain relief… used for mild-moderate pain
  3. anti-pyrexic
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12
Q

In which patients are NSAID ADRs most likely to occur?

A 
- long term use in elderly
HRH:
- heart failure
- renal disease
- hepatic cirrhosis
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13
Q

How are NSAIDs transported in blood? What is their 1/2 life?

A
  • Many heavily bound (90-99%) to plasma protein - acts as reservoir and important in drug-drug interactions.
  • 2 groups of 1/2 lives: <6hrs and >10hrs.
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14
Q

Name possible GI ADRs from NSAIDs and explain why these occur.

A
  • GI ADRs in 35% users, esp. long term. Often asymptomatic.
  • Include varying degrees of:
    1. stomach pain
    2. nausea
    3. heart burn
    4. gastric bleeding
    5. ulceration
  • Occur due to inhibition of gastric COX-1 PGE2, which normally stimulates cytoprotective mucus secretion throughout GI tract, reduces acid secretion and promotes mucosal blood flow.

(Offset long-term GI AGRs with PPIs or misoprostol, but have own ADRs).

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15
Q

Describe possible renal ADRs and explain why these occur.

A

PGE2 and PGI2 normally maintain renal blood flow (dilation of renal afferent arteriole).

If inhibited by NSAIDs then GFR decreases… Na/K/Cl and H2O retention… increased hypertension risk and kidney injury.

Is esp. important if renal perfusion already impaired (heart disease, renal failure, hepatic cirrhosis), esp. in neonates/elderly.

Dose and use dependent risk increase.

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16
Q

Why can NSAIDs affect bleeding time? With which NSAID is this particularly the case?

A

Inhibition of COX-1 mediated production of thromboxane A2… cannot promote platelet aggregation… increased bleeding time and bruising haemorrhage.

Esp. seen with aspirin which irreversibly inhibits COX-1 in platelets.

17
Q

Describe 2 types of hypersensitivity reactions that can occur in response to NSAIDs.

A
  1. Skin rashes (15% for some NSAIDs) - usually mild but in rare cases can get very serious Stevens Johnson syndrome (immune complex-mediated hypersensitivity response involving compromised hepatic function and rash of skin and mucous membranes)
  2. Bronchial asthma - Rx care in asthmatics (10% incidence)
18
Q

What is Reyes Syndrome?

A

Rare serious brain/liver injury in paeds after NSAIDs - usually in viral infections treated with aspirin

19
Q

Why is the use of specific COX-2 inhibitors limited?

A
  • not completely free of GI ADRs

- significant icnrease of cardiovascular ADRs with long term use - only approved for short term use

20
Q

Why are NSAIDs often prescribed in combination with opiates?

A
  1. extend range of treatable pain (act by different mechanism)
  2. reduces ADRs seen with opiates alone
21
Q

Why should different NSAIDs not be prescribed in combination?

A
  1. increases risk of ADRs
  2. can affect each others PK/PDs due to competition for plasma protein binding sites
  3. NSAIDs + low dose aspirin - compete for COX-1 binding sites… may interfere with cardioprotective action of aspirin
22
Q

Name 3 drugs that are affected by NSAIDs if prescribed in combination, and the clinical consequences if doses aren’t adjusted.

A
  1. sulphonylurea (hypoglycaemia if increased availability)
  2. warfarin (bleeding if increased availability)
  3. methotrexate (wide range serious ADRs if increased)
23
Q

Give 3 reasons why aspirin is different to other NSAIDs.

A
  1. Only NSAID to irreversibly inhibit COX enzymes by acetylation.
  2. Unique PK profile - T1/2 <30 min as rapidly hydolysed in plasma to salicylate:
    - lower doses = 1st order kinetics (dose-dependent)
    - higher doses = 0 order kinetics (risk of overdose)
  3. Widespread use as cardioprotective (low dose 75mg) and evidence for prophylactic in GI/breast cancer
24
Q

Should paracetamol be preferentially prescribed over NSAIDs for pain? for inflammation?

A
  • Is very effective for mild-moderate analgesia and fever and at therapeutic doses has much better ADR profile than other NSAIDs (= agent of choice).
  • But has virtually no anti-inflammatory action = non-opiate analgesic drug
25
Q

Describe the metabolism of paracetamol and explain how this relates to paracetamol toxicity in overdose.

A

Paracetamol metabolism (linear PKs at normal doses) mainly uses Phase II conjugation which produces glucoronide (60%) and sulphate (30%). But there is also some Phase I oxidation which produces NAPQI (10%).

NAPQI is very reactive and toxic. At normal doses is detoxified by Phase II conjugation with glutathione. Detoxification step is also linear BUT limited by glutathione availability.

At high doses paracetamol PKs become 0 order:

i. Step 1 Phase II metabolism saturated… increase Phase I production of NAPQI…
ii. Step 2 Phase II conjugation of NAPQI also saturated (insufficient glutathione)… increased unconjugated NAPQI…
iii. is a highly reactive nucleophilic which binds with cellular macromolecules/mitochondria - necrotic hepatic cell death…
iv. hepatic failure (+/- renal failure)

26
Q

Describe the management for paracetamol overdose.

A

Treatment must be given as soon as possible - guided by blood levels of drug. Is time dependent - delayed hepatoxic effects peak 72-96 hrs post-ingestion.

  • 0-4 hrs: activated charcoal orally (reduces uptake by 50-90%)
  • 0-36 hrs: start IV N-acetylcysteine (conjugating agent)
  • oral methionine if NAC cannot be given rapidly

ESA 4- Clinical Pharmacology (23 decks)

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