NSAIDs Flashcards
1
Q
What are NSAIDs?
A
- Analgesic
- Anti-pyretic
- Anti-inflammatory
2
Q
In general, what are NSAIDs used to treat?
A
- Low grade pain (chronic inflammation e.g. arthritis)
- Bone pain (cancer metastases)
- Fever (associated with infections)
- Inflammation
3
Q
What is the pharmacological mechanism behind NSAIDs?
A
- Inhibits COX
- COX-1 is constitutively active
- COX-2 is inducible by IL-1b/TNFa
- Inhibition of COX-2 reduces PGs/TXs
- Aspirin acts irreversibly on COX by acetylating the enzyme, others act reversibly
- Older generations inhibit both 1 and 2 -> can cause peptic ulcers
4
Q
What is different about paracetamol?
A
- Analgesic without anti-inflammatory effects
- Little inhibition of COX 1-3
May modulate serotonergic neurotransmission - inhibits COX-mediated generation of hydroxypeptides from AA metabolism (hydroxypeptides stimualte COX so reducing it may reduce COX activity -> less PGs so less pain)
5
Q
What is the process of NSAID’s antipyretic action?
A
- Bacterial endotoxins cause macrophages to release IL-1b
- Acts on hypothalamus to cause PGE2 release via COX2
- PGE2 elevates set point temp -> fever
- NSAIDs block PGE2 production - lowers set point temp
- Have no effect at normal body temp, only when raised
6
Q
How do NSAIDs cause analgesia?
A
- PGs sensitise and stimulate nociceptors
- Oedema produce also activates nociceptors
- PGs act synergistically with kinins and 5-HT to produce hyperalgesia
- Blocking COX reduces PGs and leads to pain relief
- COX-1,2 and 3 inhibition in CNS
7
Q
How does NSAIDs have anti-inflammatory actions?
A
- PGE2 and I2 have powerful acute inflammatory effects (arteriolar dilation, increase permabiltiy in post-capillary venules and capillary bed -> both cause influx of inflammatory mediators and cells into interstitial space)
- Inhibition of PG formation reduces redness and swelling
- NSAIDs only provide symtpomatic relied (dont cure it)
8
Q
Give 8 places that NSAIDs may act
A
CVS Skeletal GIT CNS Genital tract Kidney Lungs and resp Skin
9
Q
What cardiovascular effects do NSAIDs have?
A
- TXA2 -> platelet aggregation and vasoconstriction
- NSAIDs decrease TXA2 via COX-1 inhibition (increases bleeding time - may be problematic in childbirth or surgery)
- NSAIDs can be used prophylactically for CVS diseases
10
Q
Briefly describe clotting
A
- Damage to endothelium
- Collagen and vWF levels increase
- Platelets stick to this, and aggregate with the help of TXA2
- Fibrinogen is cleaved to fibrin, which forms a mesh holding it all together, and decreases movement of microbes
- When healed, plasmin breaks the clot so that there isnt thrombosis etc
11
Q
Why is aspirin beneficial in cardiovascular disorders?
A
- COX-1 (platelets) is constitutively active, COX-2 (endothelial cells) is inducible by cytokines
- Aspirin blocks both, and so both PGI2 and TXA2 are reduced
- New COX can be made in endothelial cells, so more PGI2 can be made by COX-2.
- However there is no protein synthesis in platelets, so no more COX-1 synthesis, so no more TXA2
- Gives less irritant effects, benefits of PGI2 and PGE2 isnt lost (so promotes blood flow, mucus and bicarbonate secretion)
12
Q
What actions do NSAIDs have on the skeleton?
A
- PGs contribute to swelling and pain in arthritis
- Arteriolar dilation, increased vascular permability and hyperalgesia
- NSAIDs thus diminish these effects
13
Q
What actions do NSAIDs have on the GI tract?
A
- PGE2 and I2 are important in protecting the gastric mucosa (stimulate mucus secretion and inhibit acid secretion
- NSAIDs decrease these protective mechanisms -> bleeding and ulcerations
- Also increase LT production as more AA can be converted by lipoxygenase pathway
- Can avoid gastric side-effects with selective COX-2 inhibitors (COX-1 in gut)
14
Q
Give 4 examples of COX-2 selective agents
A
Celecoxib
Valdecoxib
Etoricoxib
Rofecoxib
15
Q
which is the most selective?
A
Etoricoxib
16
Q
Why was rofecoxib withdrawn?
A
Too many CV effects
17
Q
What is a contraindication of COX-2 inhibitors?
A
- Patients with ishaemic heart disease and/or cerebrovascular disease (stroke), and peripheral arterial disease
18
Q
What do NSAIDS do in CNS?
A
- Inhibit pyrexia
- In overdose they produce paradoxical hyperpyrexia, stupor and coma
- Increases metabolism and metabolic acid production
- Risk of Reye’s syndrome (brain and liver damage) in kids with influenza or chicken pox
19
Q
What do NSAIDs do in the genital tract?
A
- PGs cause pain and smooth muscle spasm during menstruation- NSAIDs help pain
- PGE2 and F2a important in uterine contractions in childbirth - NSAIDs delay contraction
- Many NSAIDs increase post partum blood loss due to TXA2 inhibition
20
Q
What do NSAIDs do in the kidney?
A
- Vasodilator PGs (E2/I2) regulate renal blood flow
- NSAIDs thus reduce renal blood flow - chronic renal injury may result
- Effectiveness of some antihypertensive drugs is reduced because of it
- Inhibition of COX-2 decreases Na excretion and increases intravascular volume
- 2/3mmHg BP rise average
21
Q
How do NSAIDs affect the respiratory tract?
A
- PGs have constrictor and dilator effects on airway smooth muscle, but NSAIDs have no effect on normal tone
- But NSAIDs must be avoided/ used with caution in asthma
- Blocking COX shifts metabolism of AA to lipoxygenase pathway - increases LTs and so increases mucus secretion and strong chemotaxis of neutrophils
- At toxic doses, aspirin initially stimulates respiration - stimulates respiratory centre and uncouples OXPHOS. Respiratory alkalosis caused by hyperventilation - CO2 washout from lungs
22
Q
What are some other indications of NSAIDS?
A
- Helps to close patent ductus arteriosus
- Decreases colonic polyps and prevents colon cancer
- Post-op pain relief
- May decrease alzheimers risk
23
Q
What is ulcerative colitis?
A
Inflammation of bowel
24
Q
How do we treat UC?
A
- Caused by increased PGs -> inflammation
- Reduce symptoms then maintain remission
- Aminosalicylates (sulfasalazine and mesalazine) first line
- Decrease inflammation for mild UC
- Short-term treatment of flare-ups
25
Q
What is the mechanism of action of sulfasazine?
A
- A prodrug, metabolised by bacteria in the colon to 5-aminosalicylic acid and sulfapyridine
- Reduces synthesis of eicosanoids by blocking COX and LOX
26
Q
What side effects does sulfasalazine have?
A
- Indigestion, nausea, abdominal pain, diarrhoea
- Dizziness, headaches, tinnitus, sleeping difficulties
- Coughing, itchy rash
27
Q
Why may you use NSAIDs for gout?
A
- Gout is an accumulation of uric acid crystals in joints - causes painful inflammation
- Want to reduce the pain
28
Q
Give 3 examples of anti-gout drugs
A
Naproxen
Diclofenac
Indomethacin
29
Q
What is the mode of action of naproxen?
A
- Inhibits COX1/2 -> lower PGs
- Exhibits analgesic, anti-inflammatory and anti-pyretic activity
- Inhibits platelet aggregation
