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sa clinical pharmacology & therapeutics > S8) NSAIDs > Flashcards

S8) NSAIDs Flashcards

1
Q

What is the principal action of non-steroidal anti-inflammatory drugs?

A

Principle action – key enzymes in prostaglandin synthesis

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2
Q

What are the three primary therapeutic effects of NSAIDs?

A
  • Analgesia
  • Anti-Inflammatory
  • Antipyretic
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3
Q

Why do NSAIDs commonly have short half lives?

A

Short half lives allows fine control of the signalling response

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4
Q

How are prostaglandins synthesised?

A

Prostaglandins are synthesised from arachidonic acid

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5
Q

Identify two types of prostaglandins

A
  • Prostacyclins
  • Thromboxanes
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6
Q

Describe the prostaglandin synthesis pathway

A

Prostaglandins are synthesised from cell membrane phospholipids and arachidonic acid and thereafter catalysed by COX-1/2 to produce specific PG enzymes

→ they are produced locally and on demand

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7
Q

PG ‘E’ is the most important in mediating the inflammatory response.

Identify four of its functions

A
  • Vasodilation
  • Hyperalgesia
  • Fever
  • Immunomodulation
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8
Q

PG synthesis by COX -1 has major cytoprotective role in three locations.

Identify them

A
  • Gastric mucosa
  • Myocardium
  • Renal parenchyma
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9
Q

What is the half life of PG and what is the significance of this for NSAIDs?

A
  • PG t1/2 short (10 mins) – need constant synthesis
  • Due to its constitutive expression, most ADRs caused by NSAIDs are due to COX-1 inhibition
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10
Q

What induces COX-2 expression and where is it expressed?

A
  • COX-2 expression induced by inflammatory mediators such as bradykinin
  • COX-2 appears to be constitutively expressed in parts of the brain and kidney
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11
Q

How do the main therapeutic effects of NSAIDs occur?

A

Main therapeutic effects of NSAIDs occur via COX-2 inhibition

this reduces the amount of prostaglandin, prostacyclin and thromboxane

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12
Q

Illustrate how differences in COX-1 and COX-2 tunnel for selective inhibition by different NSAIDs

A
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13
Q

Explain prostaglandin binding with receptors

A
  • Prostaglandins bind with GPCRs
  • Specific actions depend on PG receptor types

For PG E, at least four main types: EP 1-4

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14
Q

In four steps, describe how prostaglandins act as inflammatory response mediators

A

⇒ Range of autacoids and prostanoids released from local tissues/blood vessels post injury

⇒ Autacoid release also induces expression of COX-2

⇒ Synergise with other autacoids (bradykinin/histamine)

⇒ PGs act as potent vasodilators & combine permeating effects of bradykinin(vasodialator)/histamine(vasodialation)

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15
Q

State the effect of prostaglandin release post injury at the following receptors:

  • EP2 receptor Gs
  • EP1 receptor Gq
A
  • EP2 receptor Gs – ↑ vasodilation
  • EP1 receptor Gq – ↑ peripheral nociception
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16
Q

With regards to sensitising peripheral nociception, describe the three effects of GPCR activation by EP1

A
  • Increased neuronal sensitivity to bradykinin
  • Inhibition of K+ channels
  • Increased Na+ channels sensitivity

All act to increase afferent ‘C’ fibre activity (carry pain stimuli)

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17
Q

In four steps, expain how peripheral sensitisation occurs

A

⇒ EP 1 binding leads to ↑ ‘C’ fibre activity

⇒ ↑ intracellular [Ca2+]

⇒ Neurotransmitter release

⇒ Other autacoids involved to ↑ sensitivity

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18
Q

In terms of nociception, illustrate the relationship between allodynia and hyperalgesia

A
  • Allodynia is pain due to a stimulus that does not usually provoke pain
  • Hyperalgesia is increased pain from a stimulus that usually provokes pain
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19
Q

In four steps, explain how sensitising central nociception occurs

A

⇒ Increased sustained nociceptive signalling peripherally ↑ cytokine levels in dorsal horn cell body

⇒ ↑ COX-2 synthesis and ↑ PGE<strong>2</strong> synthesis

⇒ PGE2 acts via local EP2 receptor (Gs type)

⇒ ↑ sensitivity and discharge rate of secondary interneurones

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20
Q

In four steps, explain how prostaglandins lead to a state of pyrexia

A

⇒ Bacterial endotoxins stimulate macrophage release of IL-1

⇒ IL-1 stimulates PGE2 synthesis within hypothalamus

⇒ PGE2 acts via EP3 receptor (Gi type)

⇒ ↑ heat production and ↓ heat loss

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21
Q

The main therapeutic effects achieved via COX-2 inhibition.

Briefly, explain how this occurs

A
  • Pharmacological action for nearly all NSAIDs via competitive inhibition of COX-1 and COX-2
  • Occupation of COX-1 /2 hydrophobic channel by NSAID competes with AA site occupation
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22
Q

How are NSAIDs administered?

A

Typically given orally but many topical preparations for soft tissue injury

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23
Q

Which pharmacokinetics pattern do NSAIDs illustrate?

A

Linear pharmacokinetics within therapeutic dose range

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24
Q

There are two groups of NSAIDs according to half lives.

Identify them

A
  • T1⁄2 < 6hrs
  • T1⁄2 >10 hrs
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25
Q

How are NSAIDs transported in the blood?

A

Many heavily bound to plasma protein (90-99%)

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26
Q

Describe the therapeutic use of NSAIDs as an anti-inflammatory

A

Very wide use in musculoskeletal disorders – rheumatoid / osteoarthritis

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27
Q

Describe the therapeutic use of NSAIDs as an analgesic

A
  • Used for mild to moderate pain accompanying many disease states
  • Universal use in Hospitals / OTC
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28
Q

Inhibition of COX-1 constitutive PG synthesis leads to many side effects.

Indicate which patient group this usually affects

A

Long term use in elderly – particularly associated with iatrogenic morbidity and mortality. they are more likely to get poetic ulcers and at risk of dyspepsia (indigestion)

29
Q

Renal ADRs occur in compromised individuals with HRH or hypovolaemia.

What is HRH?

A
  • Heart failure
  • Renal disease
  • Hepatic cirrhosis
30
Q

The major ADRs are seen in stomach /GI tract.

Identify some

A
  • Stomach pain
  • Nausea
  • Heartburn
  • Gastric bleeding
  • Ulceration
31
Q

Explain why a gastric ADR can occur by the selective inhibition of COX-1

A

Gastric COX-1 PGE2 stimulates cytoprotective mucus secretion throughout GI tract, reduce acid secretion and promote mucosal blood flow.

→ now reduced mucus secretion and more acid so enhanced cytotoxicity and hypoxia

32
Q

Explain why a renal ADR can occur due to NSAIDs

A
  • PGE2 and PGI2 maintain renal blood flow
  • If reduced by NSAIDs then GFR decreases – further risk of renal compromise (especially neonates/elderly)

→ shouldn’t give in people with CKD and heart failure if they rely on vasodialation for renal perfusion

33
Q

Apart from GI and renal symptoms, identify some other NSAID ADRs

A
  • Vascular – decreased bleeding time, bruising haemorrhage
  • Hypersensitivity – skin rashes, bronchial asthma
  • Rare serious brain/liver injury – usually in viral infections treated with aspirin risk of damage
34
Q

What are the therapeutic benefits from combining NSAIDs with low dose opiates?

A
  • Extends therapeutic range for treating pain
  • Reduces ADRs seen with opiates alone
35
Q

Identify three highly protein bound drugs affected by NSAIDs

A
  • Sulphonylurea
  • Warfarin
  • Methotrexate
36
Q

What is the effect of NSAIDs given in combination with aspirin?

A

NSAIDs + low dose Aspirin – compete for COX-1 binding sites and may interfere with cardioprotective action of Aspirin

37
Q

What is the result of multiple NSAIDS given in combination?

A
  • Increase risk of ADRs – often occurs due to self medication with NSAIDs
  • Affect each others PK/PDs due to competition for plasma protein binding sites
38
Q

Describe how aspirin acts uniquely in the body

A
  • Only NSAID to irreversibly inhibit COX enzymes by acetylation
  • T1⁄2 < 30 minutes rapidly hydrolysed in plasma to salicylate
39
Q

Why is paracetamol a unique non NSAID?

A

Paracetamol is a unique ‘non NSAID’ as it has virtually no anti-inflammatory action – more of a NOAD (non-opiate anagelsic drug)

40
Q

When is paracetamol used?

A

Paracetamol is very effective for mild/moderate analgesia and fever

41
Q

What is the therapeutic dose for paracetamol?

A

Therapeutic dose: 8 x 500 mg tablets/day

42
Q

In normal doses, paracetamol displays linear pharmacokinetics.

How is it metabolised?

A
  • Mainly Phase II Conjugation – Glucoronide 60%, Sulphate 30%
  • Some Phase 1 Oxidation – NAPQI 10%
43
Q

NAPQI is very reactive and toxic.

How is it detoxified?

A
  • At normal doses, NAPQI is detoxified by Phase II conjugation with Glutathione
  • Linear detoxification step limited by availability of Glutathione
44
Q

What is a toxic dose of paracetamol?

A

Single doses > 10 g (20 tablets) potentially fatal

45
Q

At high doses, paracetamol pharmacokinetics become zero order.

Describe paracetamol metabolism at high doses

A
  • First step Phase II metabolism saturated
  • ↑ Phase I production of NAPQI
  • Phase II conjugation of NAPQI with glutathione rate limited – also saturated
46
Q

Paracetamol overdoses are time dependent – delayed hepatoxic effects peak 72 - 96 hrs post ingestion.

How can this be treated?

A
  • 0-4hrs – activated charcoal orally reduce uptake by 50-90%
  • 0-36 hrs – start N-Acetylcysteine IV
  • Methionine orally (if NAC cannot be given promptly)
47
Q

what is the role of PGE2

A

involved in acid secretion in parietal cells

48
Q

what is the role of PGF2a

A
49
Q

what is the role of PGD2

A
50
Q

what is the role of PGI2

A

cytoprotective in the CVS

  1. binds to platelet receptors and increases cAMP in platelets
  2. this then releases lots of ca
  3. this reduces platelet aggregation by blocking GP IIb/IIIa
51
Q

what is the role of TXA2

A

normally bad for the CVS

52
Q

why is a fine balance between the different prostaglandins so important

A

TXA2 and PGI2 have apposing vascular effects, so must have a fine balance between the two

53
Q

briefly explain what the difference is between the two COX-1 and COX-2 enzymes is

A

COX-1: active across most tissues

COX-2: mostly involved in chronic inflammation

54
Q

how do NSAIDs lead to analgesia

A
  • block PGE2 overall reducing peripheral pain
  • reduced synthesis of PGE2 in dorsal horn
  • reduction in amount if neurotransmitter
  • reduce excitability of neurones in pain relay pathway
55
Q

how can NSAIDS be used as an antipyretic

A
  • inhibition of hypothalamic COX-2 where cytokine induced prostaglandin (PGE2) is synthesised
56
Q

what does COX selectivity mean?

A
  • NSAIDS are differentiated by their selectivity towards the two different COX enzymes
  • since there were lots of ADRs with cox-1 inhibitors more NSAIDS with a higher selectivity to COX 2 came about
57
Q

which people should you avoid giving NSAIDS too?

A

elderly, prolonged use, smoking, alcohol, history of peptic ulceration

58
Q

drug interactions of NSAIDS

A

aspirin, glucocorticoid steroids, anticoagulants

59
Q

adverse effects of using NSAIDS on the kidneys

A
  • prostaglandins normally inhibit NA reabsorption in collecting duct (natriuresis)
  • NSAIDS inhibit this action so high Na, H20 and BP: should avoid ACEi, ARBs and diuretics
60
Q

selective cox -2 inhibitors

A
  • purpose was to avoid the homeostatic actions mediated by COX-1
  • they avoid GI bleeds and renal ADRS
  • inhibit PGI2 which can cause other ADRs
61
Q

what do all NSAIDs increase risk of

A

MI

62
Q

why do NSAIDS normally displace other bound drugs

A

→ they have a strong binding ability so can displace other drugs. Increasing free drug concentration of these other drugs

63
Q

what drugs do NSAIDs displace

A
  • sulfonylurea - cause hypoglycemia (more insulin and so reduced glucose)
  • methotrexate - hepatotoxicity
  • warfarin - more risk of bleeding
64
Q

what are some uses for NSAIDS

A
65
Q

what are some COX-2 inhibitors

A

celecoxib

etoricoxib

66
Q

how does N - Acetylycysteine help in paracetamol overdose

A

restores glutathione to remove free radicles

67
Q

Does Celecoxib present with a greater risk of GI ADRs than naproxen

A

no, it is associated with fewer GI ADRs than non-selective NSAIDS including naproxen

68
Q

difference between prostacyclins and thromboxane A2

A

sa clinical pharmacology & therapeutics (36 decks)

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