Cyclo-oxygenase inhibitors and adverse effects Flashcards
What was the basic undersatnding of COX1 and 2 in the 1990s?
COX 2 inducible enzyme
COX 1 is a constitutive enzyme with protective roles:
Gastroprotection
Haemostasis
Nephroprotection
What is the Role of COX 1 in the stomach?
COX-1 converts arachidonic acid to PGE2
PGE2 has gastroprotective roles (same with PGI2)
Vasodilate to maintain effective blood flow to GI mucosa—>increase muscous secretion/inhibit HCL secretion by parietal cells
Can co-formulate NSAIDs with misoprostol or NO releasing compounds
Why NSAIDs being weak acids is significant?
Weak acids (like NSAIDs) are non-ionized (lipid-soluble) in the acidic environment of the stomach (pH ~1–3).
This allows them to readily cross gastric mucosal membranes and be absorbed early in the GI tract.
⚡ So NSAIDs are quickly and efficiently absorbed orally, especially on an empty stomach.
So not only do NSAIDs inhibit COX-1 (reducing protective prostaglandins), but their weak acid nature makes them toxic right at the stomach lining
What is the effect of NSAIDs inhibition of COX-1 & COX-2?
COX-1: impaired platelet aggregation, Reduced mucus secretion so impaired defence —> mucosal injury and bleeding.
COX-2: reduced angiogenesis, impaired healing, increased leukocyte adhesion- more activation so mucosal injury and bleeding
Inhibition of either enzyme can promote gastric ulceration particularly in patients with other risk factors
What does activated Platelet Thromboxane A2 do?
Its a metabolite of COX 1 which stimulates:
The release of mediators from platelet granules
Aggregation in most species
Stimulates the platelet to aggregate together
Why can aspirin be used as a aselective inhibitor of platelet activation?
Proteins within a cell turnover means they’re degraded and replaced by new protein synthesis. Platelets do not make new proteins because they don’t have a nucleus so theyre are not able to make new proteins. If we inhibit COX in a platelet the thing that determines whether the platelets will start to respond normally again is how quickly they’re produced from the bone marrow.
Explain why seelctive COX-2 inhibitors increase cardiovascular risk more than non-selective COX inhibitors?
The Prothrombotic Imbalance
🧪 Prostaglandin Players:
Thromboxane A₂ (TXA₂) – made by platelets via COX-1
👉 Promotes platelet aggregation and vasoconstriction
Prostacyclin (PGI₂) – made by endothelial cells via COX-2
👉 Inhibits platelet aggregation and causes vasodilation
COX-2 inhibitors block PGI₂ production but do not block TXA₂ (because platelets rely on COX-1). ➡️ This leads to unopposed platelet activity (↑ clotting risk), vasoconstriction, and endothelial dysfunction ➡️ Result: increased risk of heart attacks, strokes, and thrombotic events
What is the traditional view of NSAID drug toxicity and the kidney?
House keeping prostoglandin production by the COX-1 enzymes within th ekidney are vasodilatory
When renal blood flow is compromised, the RAAS is activated PGI2 protects against excessive vasoconstriction
What do non selective Cox inhibitors do in hypotensive/hypovolaemic patients?
Risk of precipitating ischaemic kidney injury
Acute kidney injury can result
Anti-inflamm drugs that are COX 2 selective should be less nephrotoxic.
PGE2 & PEI2 are major Cox metabolites needed for what?
Maintain GFR in hypotensive state
Signal for renin secretion
Vasodilation of Pre-glomular microvasculature and relaxation of mesangial cells
Full expression of the pressure natriuresis response when faced with an overload of salt
Ability to maintain water and electrolyte balance in the face of water deprivation
What does PGE2 do to renal function?
Natriuretic
Decrease sodium reabsorption at the thick ascending limb of the loop of Henle
What does PGI2 do to renal function?
Autoregulation and renoprotection:
Increase renin release which casues increase aldosterone, increasing K+ excretion
Vasodilation, increases renal blood flow and GFR in stressed states
What are the side effects of COX inhibitors that is not seen in healthy individuals?
Acute decrease in GFR in hypotensive/shocked/dehydrated patients
Damage the interstitium and papillary areas of the kidney in dehydrated patients
Cause sodium retention and inhibit the action of diurectic drugs in human heart failure and hypertensive patients
Are COX 2 inhibitors safer than non-selective COX inhibitors?
First you need to know what is the physiological role of COX 2?
Development of COX 2 selective inhibitors has facilitated study of this
Clues function can be obtained from localised enzymes and manipulating physiology experimentally
Where are COX-1 localised in the kidney?
Renal vasculature (incl. afferent arteriole)
Glomerular mesangial cells
Collecting duct epithelial cells (cortex & medulla)
Where are COX-2 localised in the kidney?
Macula densa and adjacent afferent arteriole
Cortical thick ascending limb of loop of Henle
Medullary interstitial cells
What is the fucntion of COX metabolites in kidney function?
PGs protect time of stress
Maintain GFR in hypotensive state
Signal for renin secretion
Vasodilation of Pre-glomular microvasculature and relaxation of mesangial cells
Full expression of the pressure natriuresis response when faced with an overload of salt
Ability to maintain water and electrolyte balance in the face of water deprivation
When renal blood flow decreases renin secretion occurs.. what is it important for?
Autoregulation and Tubuloglomerular feedback
What is the stimuli for renin secretion?
Sympathetic nervous system activation
Low pressure in the afferent arteriole
Low chloride detected by the macula densa
Why are PGs important in maintaining GFR in volume depletion?
Prevent excessive vasoconstriction of the afferent arteriole (endothelial COX-1)
Cause relaxation of mesangial cells (COX-1)
Mediating renin secretion from the macula densa (COX-2)
What is the regulation of COX-2 in the macula densa?
Macula densa is key to detection of low filtration and low tubular flow
Constituative expression of COX-2 found on:
-Mouse, rat and rabbit macula densa
Increased expression stimulated by
-Feeding a low salt diet
- Treating with diuretics
-Treating with ACE-inhibitors
What is the evidence for the role of COX-2 in renin secretion?
No-selective COX inhibitors or COX-2 selective inhibitors prevent renin secretion in response to the low Cl- transport by macula densa
Mineralocorticoid hormones:
Tonically inhibit COX-2 expression in the macular densa (negative feedback mechanism)
Spironolactone (mineralocorticoid receptor antagonist) treatment leads to upregulation of COX-2
Where are COX-1 found in terms of regulation of water balance?
Found in epithelial cells of the collecting ducts
Where are COX-2 found in terms of regulation of water balance?
Found in the medullary interstitial cells and in the endothelial cells of the vasa recta
