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semester 4 - cpt & prescribing > 14. NSAIDs > Flashcards

14. NSAIDs Flashcards

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1
Q

how is the effect of NSAIDS achieved?

A

The therapeutic benefit of prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) is a result of inhibiting down stream products of arachidonic acid

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2
Q

how is arachidonic acid produced and where is it found?

A
  • Arachidonic acid derived primarily from dietary linoleic acid – vegetable oils converted hepatically to arachidonic acid and incorporated into phospholipids
  • Found throughout the body – particularly in muscle, brain, liver and kidney
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3
Q

what are prostanoids?

A

prostaglandins, prostacyclin and thromboxanes

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4
Q

when are prostanoids produced?

A

Prostanoids are produced locally on demand – different enzymes, different prostanoids, short half lives so fine local control

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5
Q

what is the action of prostacyclin?

A
  • Prostacyclin (PGI2) produced and released by endothelial cells – inhibits platelet aggregation
  • PGI2 binds to platelet receptors → ↑[cAMP] in platelets
  • ↑[cAMP] → ↓calcium - preventing platelet aggregation
  • ↓in platelet aggregatory agents
  • Stabilises inactive GPIIb/IIIa receptors
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6
Q

what are the 3 types of prostaglandins?

A

PGE2, PGF2α, PGD2

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7
Q

what is the effect of PGE2 and PGI2 on gastric secretion?

A
  • PGE2 cotributes to regulation of acid secretion in parietal cells - reduced acid secretion by activating GPi receptor so inhibits adenylyl cyclase so decreased cAMP
  • Prostacyclin (PGI2) contributes to maintenance of blood flow and mucosal repair
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8
Q

what receptors do prostanoids act on?

A

Prostanoids signal through many GPCRs

• Many receptors, differential expression in tissues and response

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9
Q

what enhances action of prostanoids?

A

• Often action is enhanced by local autacoids including bradykinin and histamine

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10
Q

Why is it important to have a balance between TXA2 and PGI2?

A
  • TXA2 and PGI2 have apposing vascular effects - TXA2 is a vasoconstrictor and platelet aggregator, PGI2 is a vasodilator and inhibit platelet aggregation
  • fine balance between them crucial – haemodynamic and thrombogenic control
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11
Q

Imbalance/disruption to prostanoids plays significant role in which conditions?

A

hypertension, MI and stroke risk

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12
Q

what is the advantage of Mediterranean diet?

A

• Diet rich in fish oils (Ω fatty acids) – “The Mediterranean diet” proposed to lead to conversion to TXA3 and PGI3 – better prostanoids – lower incidence of CVD?

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13
Q

what are the Two functional isoforms of Cyclooxygenase enzymes and where are they found?

A

COX-1 constitutively active across most tissues
COX-2 inducible – mostly – in chronic inflammation
constitutively in brain, kidney and bone

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14
Q

What are the homeostatic functions of COX1 and 2?§

A 
COX1:
- GI protection
- platelet aggregation
- vascular resistance
COX2:
- renal homeostasis
- tissue repair and healing
- uterine contractions
- inhibition of platelet aggregation
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15
Q

What are the pathological functions of COX1 and 2?

A 
COX1:
- chronic inflammation
- chronic pain
- raise BP
COX2:
- Chronic inflammtion
- chronic pain
- fever
- blood vessel permeability
- tumour cell growth
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16
Q

what are NSAIDs given for?

A

varying antipyretic, analgesic and anti-inflammatory properties

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17
Q

what is the single common mode of action of NSAIDs?

A

inhibition of COX ↓prostaglandin, prostacyclin and thromboxane synthesis
• Compete with arachidonic acid for hydrophobic site of COX

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18
Q

How do NSAIDs provide analgesia?

A
  • Inhibition reduces peripheral pain fibre sensitivity by blocking PGE2
  • centrally: ↓PGE2 synthesis in dorsal horn - ↓neurotransmitter release → ↓excitability of neurons in pain relay pathway
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19
Q

When is full analgesic effects of NSAIDs achieved?

A
  • efficacious after first dose

- but full analgesia after several days dosing

20
Q

How do NSAIDs provide anti-inflammatory effects?

A
  • ↑COX activity → prostaglandin mediated increase in vasodilatation and oedema
  • NSAIDs reduce production of prostaglandins released at site of injury
  • Vasodilation in post capillary venules contributes to increased permeability and local swelling NSAIDs inhibit this
  • possible COX independent pathway, some effects ↓ROS by oxygen scavenging properties?
21
Q

do NSAIDs treat the inflammatory condition ?

A

Symptomatic relief with COX inhibition – little effect on underlying chronic condition

22
Q

How do NSAIDs provide anti-pyretic effects?

A
  • Pyrogens (e.g. IL1, 6) induce prostaglandin (PGE2) synthesis in the theromoregulatory centre in the hypothalamus leading to increase in set point temperature and fever
  • Inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis is elevated results in a reduction in temperature
23
Q

how are NSAIDs differentiated?

A
  • NSAIDs are differentiated by their selectivity

* High prevalence of ADRs attributable to COX-1 led to selective COX-2 inhibitors (coxibs)

24
Q

list the COX1 selective NSAIDs

A

aspirin(low dose)

25
Q

list the NSAIDs with increasing COX 2 selectivity

A

ibuprofen, naproxen, diclofenac, celecoxib, etoricoxib

26
Q

What are some GI ADRs with COX inhibitors?

A
  • Dyspepsia, nausea, peptic ulceration, bleeding and perforation
  • Exacerbation of inflammatory bowel disease
27
Q

why do NSAIDs cause GI ADRs?

A
  • ↓mucus and bicarbonate secretion, ↑acid secretion

* ↓mucosal blood flow → enhanced cytotoxicity and hypoxia

28
Q

what are the GI warnings, contraindications of NSAIDs?

A

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

29
Q

what are some important GI drug interactions of NSAIDs?

A

aspirin, glucocorticoid steroids, anticoagulants (PPI should be considered)

30
Q

What are some renal ADRs with COX inhibitors?

A
  • NSAIDs produce reversible ↓GFR ↓renal blood flow Therapeutic dose in healthy person – less issues
  • Prostaglandins inhibit sodium absorption in the collecting duct – natriuresis – NSAIDs inhibit this action therefore ↑Na, ↑H2O, ↑BP ~5mmHg
31
Q

what are the renal warnings, contraindications of COX inhibitors?

A

More likely in underlying CKD, heart failure
where there is greater reliance on prostaglandins and prostacyclin for vasodilatation of afferent arteriole and renal perfusion

32
Q

what are some important renal drug interactions of NSAIDs?

A

ACEi,ARBs, diuretics

33
Q

why should NSAIDs and ACEi/ARBs not be used together?

A

when there is a decrease in renal blood flow, there is an increase in vasodilating prostaglandins to increase blood flow however using NSAIDs inhibit prostaglandins production so blunts this response

when there is a decrease in renal blood flow, renin is released which causes efferent arteriole constriction by angiotensin II to increase GFR however this response is blunted by ACEi/ARBs which inhibit angiotensin II production.

therefore, the combined used of NSAIDs and ACEi/ARBs restricts both dilation of afferent arteriole and constriction of efferent arteriole resulting in reduced GFR.

34
Q

Give 2 examples of selective COX-2 inhibitors.

A

celecoxib, etoricoxib

35
Q

what is the advantage of COX-2 selective inhibitors?

A
  • The intention of COX-2 inhibitors was to avoid inhibition of homeostatic actions mediated by COX-1
  • Less inhibitory action on COX-1 but selectivity for COX-2 varies among drugs X
  • Less GI ADRs, renal ADRs similar to non-selective
36
Q

what is the disadvantage of COX-2 selective inhibitors?

A

• COX-1 is used for thromboxane A2 pathway and COX-2 for prostacyclin pathway
COX-2 selective inhibitors do not share antiplatelet action but inhibit PGI2 - potentially leading to unopposed aggregatory effects of thromboxane A2 which is bad for CVS
• Some evidence of less analgesic effect

37
Q

can COX-2 inhibitors be useful when monitored in severe osteo and rheumatoid arthritis for longer term treatment?

A

yes

38
Q

what does all NSAIDs have an increased risk of?

A

risk of MI including in low risk people

39
Q

what is the association between NSAIDs and protein binding?

A

• NSAIDs Displace other bound drugs → increasing free drug concentration
• Particularly high protein bound drugs e.g.
- sulfonylurea –> hypoglycaemia
- methotrexate -> accumulation and hepatotoxicity
- warfarin –> increased risk of bleeding

40
Q

What are some indications for use of NSAIDs?

A
  • Inflammatory conditions - joint and soft tissue
  • Osteoarthritis - topical NSAID and paracetamol should be tried first
  • Postoperative pain
  • Topical use on cornea
  • Menorrhagia (moderate reduction in blood loss)
  • Low dose aspirin for platelet aggregation inhibition
  • Opioid sparing when used in combination
41
Q

What are some contraindications for use of NSAIDs?

A
  • Cardiovascular disease – risk
  • Renal function - age
  • GI disease - previous use of NSAIDs
  • DDIs – ACEi and ARBs, steroids, diuretics, methotrexate, warfarin (not exhaustive list)
  • Level of pain, pyrexia, level of inflammation
  • Third trimester of pregnancy – not sustained use – delayed labour and early closure of ductus arteriosus
42
Q

what is the advice when prescribing NSAIDs?

A

Lowest effective dose for the shortest time necessary taking into account patient specific risk factors

43
Q

What should paracetamol be used for?

A

Mild to moderate analgesia and fever

44
Q

what is the mechanism of paracetamol?

A

• mechanism still not completely elucidated – 150+ years after discovery! COX-2 selective inhibition in CNS (spinal chord) - ↓pain signals to higher centres
peroxidases in peripheral inflammation so very little anti-inflammatory action

45
Q

What is the half life of paracetamol?

A

2 hrs

semester 4 - cpt & prescribing (25 decks)

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