NSAIDs Flashcards
What are NSAIDs used for?
What are they used for, how are they different to older gen NSAIDs etc etc
– Low grade pain (chronic inflammation, e.g. arthritis)
– Bone pain (cancer metastases)
– Anti-pyretic, so treats fever, Inflammation
Aspirin acts irreversibly on COX; others act reversibly= significant in CVD prophylaxis
Older generation NSAIDs inhibit both COX-1 and COX-2
Why is paracetomol not an NSAID?
Analgesic w/o anti-inflammatory effects
Little inhibition of COX-1 or COX-2 in peripheral tissue
Weakly inhibits COX-3 in CNS – this doesn’t explain all effects
How bacteria cause fever? NSAIDs have antipyretic action, what is meant by this?
Bacterial endotoxins produced in infection stimulate macrophages to release IL-1β
IL-1β acts on the hypothalamus to release PGE2 (via COX-2)
↑PGE2 depresses temp sensitive neurons–> increases set point= fever
NSAIDs block PGE2 production- lowers fever
NSAIDs have no effect on normal body temp
How can PGs cause pain?
NSAIDs have analgesic action, what is meant by this and what is it useful for?
PGs sensitise + stimulate nociceptors.
Oedema due to inflammation also activates nociceptors
PGs interact w kinins, 5-HT, histamine to produce hyperalgesia (↑ pain sensitivity)
Blocking PG production leads to pain relief
Useful for inflammatory pain (PGs/TXs), e.g. arthritis, toothache, headache (NSAIDs inhibit PG-mediated vasodilatation)
What are the actions of PGE2 and PGI2?
Give the anti inflammatory action of NSAIDs, ref aspirin as well
PGE2 and PGI2 dilate arterioles, increasing BF
They also increase permeability in post-capillary venules
Both increases inflammatory mediators into interstitial space
Aspirin inhibits NF-kB activation which reduces redness + swelling
NSAIDs only relieve symptoms, not cure inflammation cause
Aspirin inhibits both COX-1 and COX-2.
Why is aspirin beneficial in CVD?
COX-1 is in platelets, and its inhibition by aspirin blocks TXA2, which promotes clotting. Platelets cannot make new COX enzymes (no nucleus)–> prolonged TXA2 inhibition and reduced platelet aggregation.
COX-2 in endothelial cells lining blood vessels.
BUT these can make new COX enzymes (nucleus) and continue producing PGI2, a vasodilator that counteracts TXA2 mediated vc and aggregation.
Hence: less irritant effects, PGI2 and PGE2 benefits not lost
How are the PGs cytoprotective?
Explain the effects of NSAIDs on the GI tract
PGE2/PGI2 stimulate mucus secretion, inhibit gastric acid secretion
NSAIDs are acidic and decreases these cytoprotective mechanisms
↓ mucus secretion, ↓ HCO3-, ↑ acid secretion
↑ LT production, ↑ blood loss
Nausea, dyspepsia, GI contraction (COX-1 inhibition)
Interfere w tissue healing (COX-2 inhibition)
What are COX2 selective agents? Give drug examples
Etoricoxib= most selective COX-2 inhibitor
Decreases PGI2 in blood vessels. No effect on TXA2
Not suitable for RA/osteoarthritis; use meloxicam, etodolac instead
Diclofenac (NSAID)= selective for COX-2, but inhibits COX-1 in GIT → ulcers
COX-2 inhibitor + NSAID will lead to serious ulcer!
Diclofenac= less analgesia compared to other NSAIDs bc it inhibits COX-3 in CNS less
What is the effect of NSAIDs on the CNS?
NSAIDs inhibit pyrexia - therapeutic use
BUT in overdose NSAIDs cause paradoxical hyperpyrexia, stupor and coma
↑ metabolism and ↑ metabolic acid production
Reye’s syndrome risk (brain & liver damage) when used in children w influenza or chicken pox
What is the effect of NSAIDs on the GU system and in pregnancy?
PGs cause pain + sm spasm in menses, NSAIDs treat this. Mefenamic acid also reduces blood loss
NSAIDs may be useful in primary dysmenorrhoea
PGs (PGE2 and PGF2α) - important in uterine contractions in childbirth
Side effects: NSAIDs delay contractions/labour
Increases post partum blood loss bc TXA2 production prevented
What is the effect of NSAIDs on the kidney and on blood pressure?
Vasodilator PGs (E2/I2) regulate renal blood flow, so NSAIDs reduce RBF—> may cause AKI
NSAID inhibition of COX-2 reduces PGE2 –> decreased Na excretion and increased intravascular volume. This can reduce efficacy of antihypertensives–> BP rises
Average BP rise = 3/2 mmHg, but varies
Give the effects of NSAIDs on the resp system when a toxic dose is given
At toxic doses aspirin stimulates the resp center in the medulla, leading to an increase in resp rate and depth. This can result in hyperventilation.
At high concs, aspirin can uncouple oxidative phosphorylation, disrupting ATP production of ATP. This can trigger compensatory responses inc RR increase
This results in respiratory alkalosis characterized by decreased C02 and increased blood pH.
What is ulcerative colitis?
Describe the drug treatment for ulcerative collitis
Ulcerative colitis = inflammation/swelling and sores of bowel lining
Caused by ↑ PGs → inflammation
First-line treatment: aminosalicylates (sulfasalazine and mesalazine)
↓ inflammation for mild or moderate ulcerative colitis.
Short-term treatment of flare-ups, good long term to maintain remission.
Describe the mechanism of action of sulfasalazine
Metabolised to 5-aminosalicylic acid (5-ASA), and sulfapyridine
This blocks COX and lipoxygenase–> less eicosanoid synthesis
Some evidence that COX and lipoxygenase activities are high in ulcerative colitis
What are the side effects of sulfasalazine?
Side effects: Indigestion, vomiting, abdominal pain, diarrhoea
Dizziness, headache, difficulty sleeping, tinnitus
Coughing, itchy rash, sore mouth, may affect taste
Describe gout and anti-gout drugs
High concs of uric acid in the blood (hyperuricemia) cause tiny grit-like crystals to collect in the joints.
This irritates the joint tissues–> inflammation, pain
Anti-gout drugs: allopurinol; naproxen, diclofenac and indomethacin
