NSAIDs Flashcards
What are the 2 different pathways arachidonic acid can follow?
Lipoxygenase pathways
Prostanoids

What are the effects of prostanoid thromboxane A2?
- Platelet aggregation
- Vasoconstriction
- Affects macrophages
What are the effects of prostanoid PGI2? (prostacyclin)
- Inhibits platelet aggregation
- Vasodilation
- Affects endothelium of kidney and brain
When are prostanoids produced?
Prostanoids are produced on demand by different enzymes
Where is arachadonic acid derived from?
Linoleic acid (vegetable oils)
Converted hepatically to arachidonic acids and incorporated into phospholipids
Where is arachadonic acid mainly found within the body?
Found throughout but main sites; brain, muscle and liver
Which prostanoid is generally good for the stomach?
PGE2

Which prostanoid causes pain, inflammation and pyrexia?
PGF 2-alpha

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

What are the 2 isoforms of cycloxygenase and when is each active?
COX-1 is constitutively active across most tissues
COX-2 is inducible in chronic inflammation. constitutively active in brain, kidney & brain
How do COX -1 and COX -2 differ structurally?
COX 2 has a larger, more flexible substrate channel where inhibitors can bind

What are the homeostatic functions of COX 1 and COX 2?
COX 1:
- GI protection (PGE2)
- Platelet aggregation
- Vascular resistance
COX 2:
- Renal homeostasis
- Tissue repair and healing
- Reproduction (uterine contractions)
- Inhibition of platelet aggregation
What are the pathological functions of COX 1 and COX 2?
COX 1:
- Chronic inflammation
- Chronic pain
- Raised blood pressure
COX 2:
- Chronic inflammation
- Chronic pain
- Fever
- Blood vessel permeability
- Tumour cell growth
What type of receptors do prostanoids acts on?
GPCR mediated receptors
How does a diet rich in fish oils (omega fatty acids) cause lower incidence of cardiovascular disease?
Omega acids convert TXA3 → PGI3
A form of prostanoid that’s better for the CVS
What is the single common mode of action of NSAIDs?
Inhibition of COX enzyme (either 1,2 or both)
Decreases prostaglandin, prostacylin and thromboxane synthesis

How do NSAIDs provide analgesia?
- Block PGE2 synthesis in the dorsal horn which reduces peripheral pain fibre sensitivity
- reduced neurotransmitter release
- reduced excitability of neurones in pain relay pathway

When do the analgesic effects of NSAIDs have the greatest effect?
- Greatest efficacy if inflammed
- Efficacious after first dose but full effect comes after several days dosing
How do NSAIDs exert their anti-inflammatory effects?
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
How do NSAIDS exert their antipyretic effects?
- PGE2 affects the thermoregulatory centre in they hypothalamus
- Inhibition of hypothalamic COX-2 reduces temperature

Which form of COX inhibition has more adverse drug reactions?
COX 1 inhibition leads to greater ADR
Which NSAIDs are more selective for COX 1 vs COX 2?

What is the most common ADR for taking NSAIDs?
GI disturbance:
- Dyspepsia
- Nausea
- Peptic ulceration
- Bleeding
- Perforation
How do NSAIDs cause GI disturbances?
- Cause decreased mucus and bicarbonate secretion
- Increase acid secretion
- Decrease mucosal blood flow
- Causes enhanced cytotoxicity and hypoxia
In which patients would you use NSAIDs with caution due to their GI risk?
- Elderly
- Prolonged Use
- Glucocorticoid steroids (need to give PPI alongside)
- Anticoagulants
- Smokers
- Alcoholics
- History of peptic ulceration
- Patients with Helicobacter Pylori
How do NSAIDs cause ADRs with the kidney?
- 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)

Why can NSAIDs counterbalance the effects of anti-hypertensives when given together?
Prostaglandins inhibit Na+ absorption at the collecting duct → naturesis
When giving NSAIDs action is inhibited→ Na+ is absorbed, increases Na, H2O and BP
Name 2 NSAIDs that are selective for COX-2
Celecoxib
Etoricoxib
What are the effects of using a selective COX-2 inhibitor?
- 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

How do NSAIDs affect protein binding?
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
When would you consider using NSAIDs?
- 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)
When would paracetamol use be indicated?
For mild to moderate analgesia and fever
How does paracetamol cause toxicity in overdose?
- 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
Why can’t you give glutathione to help with paracetamol overdose?
Glutathione does not get absorbed into hepatocytes
What symptoms occur in paracetamol overdose?
- Can be asymptomatic for many hours
- Nausea, vomiting and abdominal pain first 24 hours
- Maximal liver damage 3-4 days
What drug can you give for paracetamol overdose?
N-Acetylcysteine given i.v.
Replaces glutathione levels driving phase 2 reactions
