NSAIDs Flashcards
what is inflammation?
- the active response of tissues to injury that can be either protective and beneficial or exaggerated and harmful
- inflammation is a local response at the site of injury (local inflammation can cause fever, anorexia, lethargy)
- it is a complex response, which involves: immune response, coagulation cascade and regeneration & repair processes
what is the purpose of inflammation?
function is to protect the body following injury:
- removal of injurious stimuli
(bacteria, chemical irritants, etc.)
- Removal of necrotic cells
- Containment of damage (e.g. abscessation)
- Stimulation of repair & regeneration
what 4 major changes occur during inflammation and what are the cardinal signs of inflammation?
acutely 4 major changes occur:
1. blood vessels dilate (warmth and redness)
2. blood vessels become leaky (fluid and proteins enter tissue → edema)
3. WBCs enter inflamed tissue
4. nociceptors become sensitized (pain)
produces the cardinal signs of inflammation:
- heat
- redness
- swelling
- pain
- loss of function
what are inflammatory mediators?
- upon tissue injury/infection, leukocytes rapidly produce inflammatory mediators that effect changes on blood vessles and tissues
- Eicosanoids are (mostly) pro inflammatory mediators:
1. prostaglandins
2. thromboxane
3. prostacylin
4. leukotrienes
the most effective anti-inflammatory drugs inhibit many or all of these
what is inflammatory mediators synthesis and redundancy?
synthesis:
- some mediators of inflammation are produced in advance for rapid release at a time of insult or injury (e.g. histamine exists pre-formed inside cells)
- others are synthesized at site of tissue injury in response to the injury (e.g. prostaglandins)
redundancy:
- several mediators will trigger the same inflammatory process, so inhibitors of one class of mediator may lessen but not abiolish inflammation
how do you alleviate inflammation? what are some effects of inflammation?
- in many cases, eliminating the insult will alleviate the inflammation
- in some cases, and exaggerated inflammatory reaction to a mild or harmless stimulus does more harm than good (e.g. allergies, autoimmune reactions, etc. )
- chronic inflammation stimulates fibrosis (scaring)
- depending on site, may impair vision, mobility, oxygenation, or cause seizures, arrhythmias, intestinal strictures, etc.
- anti-inflammatory therapy may be necessary if stimulus cannot be identified or eliminated
inflammation inciting causes, beneficial outcomes and harmful outcomes?
inciting causes:
- infection: bacteria/fungi, virus, parasites
- trauma
- necrosis
- immune-mediated disease
these cause inflammation → vascular responses and leukocyte responses
Beneficial outcomes:
- elimination or containment of infectious agent
- repair or regeneration of tissue
Harmful outcomes:
- loss of tissue function (temporary)
- systemic: fever, anorexia (temporary)
- scar formation impairment of organ function may be permanent
how do we reduce inflammation to reduce harmful outcomes?
non-pharmaceutical:
- ice and heat
- elevate
- lifestyle habits (sleep, food, activity level etc.)
pharmacological:
- non-steroidal anti-inflammatory drugs (NSAIDs) (Advil)
- glucocorticoids
- miscellaneous others (doxycycline)
What is the mechanism of action of aspirin? what are the main beneficial effects of NSAIDs?
- John Vane discovered the moa of aspirin in 1970s: inhibititon of prostaglandin synthesis
- aspirin is the older of the non-steroidal anti-inflammatory drugs
NSAIDs are a family of chemically disimiar drugs that produce three main benefits:
1. anti-inflammatory effects
2. antipyretic effects (fever)
3. analgesic effects
clinical use: for the relief of musculoskeletal and inflammatory pain, including post-operative pain
what is the synthesis of prostaglandins (PGs)?
- PGs are eicosanoids that exhibit diverse roles in inflammation and cellular signalling
- upon stimulation, phospholipase A releases arachidonic acid from the plasma membrane
- cyclo-oxygenase (COX) enzymes then synthesize PGs and other eicosanoids from arachidonic acid
- two main enzymes in humans: COX-1 and COX-2
what will happen with respect ti prostaglandins in the absence of inflammatory stimulus?
- COX-1 is a normal “housekeeping” enzyme present at low levels in most tissues
- COX -2 is normally present at much lower levels in most tissues, but is impotant for homeostasis in a few tissues (e.g. renal medulla, gastric mucosa)
thromboxane (TXA2) - synthesized by COX-1 in platelets
- promotion of platelet aggregation
Other PGs (PGD2, PGE2, etc.) - maintenance of tissue blood flow
- many other tissue-specific protective functions
prostacyclin (PGI2) - inhibition of platelet aggregation
- vasodilation and other protective functions
PGE2 and PGI2 also involved in gastric mucosa protection: decrease acid secretion by gastric parietal cells, increase bicarb and mucus secretion, increase vasodilation
prostaglandins and inflammation in the presence of inflammatory stimulus
- COX-2 is up regulated in reponse to plasma membrane damage or inflammatory mediator release
- COX-2 induction is a local response that occurs at the site of cell damage or mediator release
- excessive vasodilation occurs promoting inflammation: redness, swelling, heat, pain, loss of function
NSAIDs mechanism of action
NSAIDs inhibit cyclooxygenase enzymes
most NSAIDs inhibit both COX1 and COX2
- reduces synthesis of PGs, including those that promote vasodilation
- reduces blood flow to site
- reduces sensitization of nociceptors
- alleviates inflammation
what are the 3 locations where adverse effects of NSAIDs occur?
- adverse effects in gastric mucosa
- adverse effects in the kidney
- adverse effects in platelets
what is the mechanism of adverse effects of NSAIDs in gastric mucosa?
the normal protective effects of PGs in the stomach are inhibited resulting in:
- decreased blood flow, bicarb secretion and mucus secretion
- increased acid secretion
this can cause gastric bleeding +/- ulceration (the most common adverse effect associated with NSAIDs)
what is the mechanism of adverse effects of NSAIDs in the kidney?
- COX enzymes produce PGs that maintain adequete blood flow to many tissues, including the renal medulla
- excessive COX inhibition can lead to renal medullary mypoxia and papillary necrosis
- in contract to most other tissues, in which COX1 is the main homeostatic cyclooxyrgenase, COX2 is particularly important in maintaining adequate blood flow in the renal medulla
what is the mechanism of adverse effects of NSAIDs in platelets?
- only COX 1 is present in platelets
- NSAIDs inhibit the conversion of AA to thromboxane in platelets
- result is slightly increased general tendency to bleed
- excessive doses of NSAIDs can cause more pronounced bleeding (this effect can be used to our advantage; for example, aspirin is used chronically in humans to reduce myocardial infarction and stroke by slightly inhibiting platelet aggregation)
how do coxibs increase the risk of stroke and heart attack?
- regular non-selective NSAIDs inhibit ths synthesis of all COX1 and 2 products, both pro- and anti- clotting
- thromboxane (TXA2) is a potent pro-clotting molecule (promotes platelet aggregation), and its inhibition produces a greater effect than the inhibition of prostacyclin (PGI2), so the net effect is slightly in favour of bleeding
- coxibs inhibit only COX2 so less PGI2 is produced than usual, but thromboxane synthesis is not inhibited. this tips the balance in favor of intravascular coagulation and therefore stroke and myocardial infarction. these effects ar only observed after prolonged (>18 months) use
