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Clinical Pharmacology > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

What are the 2 different pathways arachidonic acid can follow?

A

Lipoxygenase pathways

Prostanoids

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2
Q

What are the effects of prostanoid thromboxane A2?

A
  • Platelet aggregation
  • Vasoconstriction
  • Affects macrophages
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3
Q

What are the effects of prostanoid PGI2? (prostacyclin)

A
  • Inhibits platelet aggregation
  • Vasodilation
  • Affects endothelium of kidney and brain
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4
Q

When are prostanoids produced?

A

Prostanoids are produced on demand by different enzymes

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5
Q

Where is arachadonic acid derived from?

A

Linoleic acid (vegetable oils)

Converted hepatically to arachidonic acids and incorporated into phospholipids

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6
Q

Where is arachadonic acid mainly found within the body?

A

Found throughout but main sites; brain, muscle and liver

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7
Q

Which prostanoid is generally good for the stomach?

A

PGE2

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8
Q

Which prostanoid causes pain, inflammation and pyrexia?

A

PGF 2-alpha

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9
Q

Which prostanoids are cytoprotective for the CVS and which are generally bad for the CVS?

A
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10
Q

What are the 2 isoforms of cycloxygenase and when is each active?

A

COX-1 is constitutively active across most tissues

COX-2 is inducible in chronic inflammation. constitutively active in brain, kidney & brain

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11
Q

How do COX -1 and COX -2 differ structurally?

A

COX 2 has a larger, more flexible substrate channel where inhibitors can bind

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12
Q

What are the homeostatic functions of COX 1 and COX 2?

A

COX 1:

  • GI protection (PGE2)
  • Platelet aggregation
  • Vascular resistance

COX 2:

  • Renal homeostasis
  • Tissue repair and healing
  • Reproduction (uterine contractions)
  • Inhibition of platelet aggregation
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13
Q

What are the pathological functions of COX 1 and COX 2?

A

COX 1:

  • Chronic inflammation
  • Chronic pain
  • Raised blood pressure

COX 2:

  • Chronic inflammation
  • Chronic pain
  • Fever
  • Blood vessel permeability
  • Tumour cell growth
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14
Q

What type of receptors do prostanoids acts on?

A

GPCR mediated receptors

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15
Q

How does a diet rich in fish oils (omega fatty acids) cause lower incidence of cardiovascular disease?

A

Omega acids convert TXA3 → PGI3

A form of prostanoid that’s better for the CVS

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16
Q

What is the single common mode of action of NSAIDs?

A

Inhibition of COX enzyme (either 1,2 or both)

Decreases prostaglandin, prostacylin and thromboxane synthesis

17
Q

How do NSAIDs provide analgesia?

A
  • Block PGE2 synthesis in the dorsal horn which reduces peripheral pain fibre sensitivity
  • reduced neurotransmitter release
  • reduced excitability of neurones in pain relay pathway
18
Q

When do the analgesic effects of NSAIDs have the greatest effect?

A
  • Greatest efficacy if inflammed
  • Efficacious after first dose but full effect comes after several days dosing
19
Q

How do NSAIDs exert their anti-inflammatory effects?

A

Without NSAIDS, COX activity causes prostaglanding release → vasodilation and oedema

Vasodilation in post capillary venules causes local swelling

With NSAIDs this is inhibited → relief is symptomatic won’t affect chronic underlying condition

20
Q

How do NSAIDS exert their antipyretic effects?

A
  • PGE2 affects the thermoregulatory centre in they hypothalamus
  • Inhibition of hypothalamic COX-2 reduces temperature
21
Q

Which form of COX inhibition has more adverse drug reactions?

A

COX 1 inhibition leads to greater ADR

22
Q

Which NSAIDs are more selective for COX 1 vs COX 2?

A
23
Q

What is the most common ADR for taking NSAIDs?

A

GI disturbance:

  • Dyspepsia
  • Nausea
  • Peptic ulceration
  • Bleeding
  • Perforation
24
Q

How do NSAIDs cause GI disturbances?

A
  • Cause decreased mucus and bicarbonate secretion
  • Increase acid secretion
  • Decrease mucosal blood flow
  • Causes enhanced cytotoxicity and hypoxia
25
Q

In which patients would you use NSAIDs with caution due to their GI risk?

A
  • Elderly
  • Prolonged Use
  • Glucocorticoid steroids (need to give PPI alongside)
  • Anticoagulants
  • Smokers
  • Alcoholics
  • History of peptic ulceration
  • Patients with Helicobacter Pylori
26
Q

How do NSAIDs cause ADRs with the kidney?

A
  • NSAIDs produce reversible decrease in GFR and Renal Blood Flow
  • In a healthy person at therapeutic doses - less issues
  • ADR more likely in underlying CKD, heart failure ( have a greater reliance on prostaglandins for vasodilation and renal perfusion)
27
Q

Why can NSAIDs counterbalance the effects of anti-hypertensives when given together?

A

Prostaglandins inhibit Na+ absorption at the collecting duct → naturesis

When giving NSAIDs action is inhibited→ Na+ is absorbed, increases Na, H2O and BP

28
Q

Name 2 NSAIDs that are selective for COX-2

A

Celecoxib

Etoricoxib

29
Q

What are the effects of using a selective COX-2 inhibitor?

A
  • Less GI ADR
  • Do not share antiplatelet action but inhibit PGI2 leading to potentially unapposed aggregatory effects of TXA2
  • Some evidence that they are less analgesic
30
Q

How do NSAIDs affect protein binding?

A

NSAIDs can displace other bound drugs → increases free drug concentration of other drugs

  • sulfonylurea → hypoglycaemia
  • methotrexate → accumulation and hepatotoxicity, leucopenia
  • warfarin → increased risk of bleeding

Likely dose adjustment needed

31
Q

When would you consider using NSAIDs?

A
  • Inflammatory conditions (joint and soft tissue)
  • Osteoarthritis
  • Post op pain
  • Menorrhagia
  • Topical use on cornea
  • Low dose aspiring to inhibit platelet aggregation
  • Cancer reduction (reduced cell proliferation by reducing nuclear transcription factors)
32
Q

When would paracetamol use be indicated?

A

For mild to moderate analgesia and fever

33
Q

How does paracetamol cause toxicity in overdose?

A
  • At normal therapeutic doses toxic metabolite NAPQI is conjugated with glutathione
  • But… hepatic glutathione is limited
  • In overdose, supply is used up and NAPQI is increased
  • NAPQI is highly nucelophilic and oxidises key metabolic enymes → ultimate cell death
34
Q

Why can’t you give glutathione to help with paracetamol overdose?

A

Glutathione does not get absorbed into hepatocytes

35
Q

What symptoms occur in paracetamol overdose?

A
  • Can be asymptomatic for many hours
  • Nausea, vomiting and abdominal pain first 24 hours
  • Maximal liver damage 3-4 days
36
Q

What drug can you give for paracetamol overdose?

A

N-Acetylcysteine given i.v.

Replaces glutathione levels driving phase 2 reactions

Clinical Pharmacology (25 decks)

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