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CPT > Session 8 NSAIDS > Flashcards

Session 8 NSAIDS Flashcards

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1
Q

How are prostanoids synthesised?

A

phospholipids are converted to arachidonic acid (by phospholipase A2)

arachidonic acids are converted to prostanoids via cyclooxygenase pathways (COX-1 or COX-2)

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2
Q

Name 5 different types of prostanoids

A
  1. PGE2
  2. PGF2a
  3. PGD2
  4. PGI2 (prostacyclin)
  5. TXA2 (thromboxane)
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3
Q

How does the therapeutic benefit from NSAIDS come about?

A

The therapeutic benefit is a result of inhibiting down stream products of arachidonic acid (i.e. stops it from being converted)

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4
Q

What is arachidonic acid derived from?

A

dietary linoleic acid e.g. vegetable oils

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5
Q

How does linoleic acid become arachidonic acid?

A

it’s converted hepatically to arachidonic acid and is incorporated into phospholipids

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6
Q

Where is arachidonic found mostly in the body?

A

muscle, brain and liver (although found throughout body!)

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7
Q

What prostanoids are involved with pain, pyrexia and inflammation?

A

PGE2
PGF2a
PGD2

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8
Q

Which prostanoid is generally good for the stomach?

A

PGE2

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9
Q

Which prostanoid is cytoprotective (CVS)?

A

PGI2 (prostacyclin)

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10
Q

Which prostanoid is generally bad for the CVS?

A

TXA2 (thromboxane)

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11
Q

Which two prostanoids require fine control as they balance each other out?

A

PGI and TXA (prostacyclin and thromboxane)

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12
Q

main difference between PGI and TXA?

A

PGI = inhibits platelet aggregation, vasodilator

TXA = promotes platelet aggregation, vasoconstrictor

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13
Q

Difference between COX-1 and COX-2?

A 
COX-1 = constitutively active across most tissues 
COX-2 = mostly inducible in chronic inflammation but also constitutively active in brain, kidney and bone
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14
Q

Homeostatic functions of COX-1 (3 things) and COX-2 (4 things)?

A

COX-1

  • GI protection (acid and mucus)
  • platelet aggregation
  • vascular resistance

COX-2

  • Renal homeostasis
  • Tissue repair and healing
  • reproduction (uterine contractions)
  • inhibition of platelet aggregation
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15
Q

Pathological functions of COX-1 and COX-2?

similarities and differences?

A 
both = chronic inflammation, chronic pain 
COX-1 = raised blood pressure
COX-2 = Fever, blood vessel permeability, tumour cell growth
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16
Q

Structural difference between COX-1 and COX-2?

What is the benefit of this?

A

COX-2 has a larger and more flexible substrate channel than COX-1
COX-2 has a larger space at the site where the inhibitors bind - allows us to target the different COX’ independently :)

17
Q

Prostaglandins signal through G-proteins. Which ones signal through which type of G-protein?

A 
PGE = Gq, Gs, Gi (E = everything) 
PGF = Gq (Fuk q) 
PGD = Gs, Gi (Do both) 
PGI = Gs 
TXA = Gq (increases Ca - vasoconstrict)
18
Q

What substances enhance the action of prostanoids?

A

bradykinin and histamine (work with signalling)

19
Q

TXA and PGI have apposing vascular effects and the fine balance between them is crucial for haemodynamic and thrombogenic control. What side effects can occur if there is an imbalance between them?

A

hypertension
MI
stroke

20
Q

What are NSAIDS mostly used for?

A

used for their analgesic and anti-inflammatory effects

21
Q

What is the single common mode of action of NSAIDs?

A

inhibition of COX which leads to decreased prostaglandin, prostacyclin and thromboxane synthesis (this can be good and bad!)

NSAIDS compete with arachidonic acid for the hydrophobic site of COX

22
Q

How do NSAIDs produce their analgesic action?

A

they have local peripheral action at the site of pain and have greater efficacy if inflammation present

inhibition reduces peripheral pain fibre sensitivity by blocking PGE(2)

Decreased PGE synthesis in dorsal horn leads to decrease neurotransmitter being released which leads to decreased excitability of neurones in the pain relay pathway

NB: efficacious after first dose but full analgesia after several days of dosing

23
Q

How do NSAIDs produce their anti-inflammatory action?

A

normally (i.e. without NSAIDs): there is increased COX activity which leads to an increase in prostaglandin’s and vasodilation and oedema - need to combat this!

NSAIDS reduce the production of prostaglandins released during injury so NSAIDS will decrease the vasodilation in post-capillary venules that normally contributes to increased permeability and local swelling

NB: this is symptomatic relief by COX inhibition but there is little effect on an underlying chronic condition

24
Q

How do NSAIDS produce their antipyretic effects/actions?

A

Normally: PGE is stimulated by pyrogens > signals to thermoregulatory centre in hypothalamus (preoptic area) > increases temperature set point > fever

Inhibition of hypothalamic COX-2 (where cytokine induced prostaglandin synthesis is elevated) results in a reduction in temperature

25
Q

How do NSAIDS produce their GI adverse drug reactions?

what do the ADR’s include?

caution with?

A

dyspepsia, nausea, peptic ulceration, bleeding and perforation

they decrease mucus and bicarbonate secretion and increase acid secretion

they reduce mucosal blood flow which leads to enhanced cytotoxicity and hypoxia

need to be careful using these drugs if you have IBD and NSAIDs can exacerbate the condition

caution in:
elderly, prolonged use, glucocorticoid steroids, anticoagulants, smoking, alcohol, history of peptic ulceration, helicobacter pylori

26
Q

What people are more likely to experience renal ADR’s from NSAIDs and why?

A

if they have underlying CKD or heart failure where there is a greater reliance on prostaglandins for vasodilation and renal perfusion (very young and elderly at greatest risk)

27
Q

How do NSAIDS lead to renal ADR’s?

A

Normally: prostaglandins inhibit sodium absorption in the collecting duct

BUT NSAIDS inhibit this action and so lead to increased sodium and water reabsorption leading to an increase in blood pressure

NSAIDs produce a REVERSIBLE decrease in GFR and renal blood flow

28
Q

What are the names of two selective COX-2 inhibitors?

A

celecoxib

etoricoxib

29
Q

Advantages and disadvantages of selective COX-2 inhibitors?

A

good

  • they have less inhibitory action on COX-1
  • less GI ADR’s
  • severe osteoarthritis / rheumatoid arthritis (can be useful when monitored)

bad

  • selectivity for COX-2 varies among drugs (not that bad but just to note!)
  • impair PGI which can lead to unopposed aggregatory effects
  • less analgesic effect (some evidence)

impartial
* renal ADR’s are similar to non-selective COX-2 inhibitors

30
Q

Considerations when prescribing NSAIDs?

A

CVD = risk
renal function - age
GI diseases - previous use of NSAIDS
DDIs - ACEi and ARBs, diuretics, sulfonylureas, methotrexate, warfarin
level of pain, pyrexia and level of inflammation

31
Q

Indications for NSAID use?

A

inflammatory conditions
osteoarthritis (use topical NSAID and paracetamol first)
postoperative pain
topical use on cornea
menorrhagia
low dose aspirin for platelet aggregation inhibitor

32
Q

mechanism of action of paracetamol?

A

still don’t really know but:

COX-2 selective inhibition in CNS (spinal cord) which leads to decreased pain signals to higher centres

little anti-inflammatory action but can be used for mild to moderate analgesia

33
Q

How can paracetamol produce toxic effects?

A

paracetamol is converted to NAPQI by phase 1 CYP’s

at normal therapeutic doses, NAPQI is conjugated with glutathione = harmless
BUT hepatic glutathione is limited so if you take too much paracetamol, NAPQI can’t all be conjugated!

NAPQI is highly nucleophilic and oxidises key metabolic enzymes leading to cell death (necrosis and apoptosis)

34
Q

How much paracetamol is sufficient to cause irreversible damage?

A

150mg/kg

35
Q

What drug do you give if you suspect a paracetamol overdose?

A

N-acetylcysteine

it drives phase 2 metabolism and decreases toxic NAPQI levels by donating thiol groups (replaces glutathione)

CPT (23 decks)

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