NSAIDs

Question 1

what is inflammation?

Answer 1

• 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

Question 2

what is the purpose of inflammation?

Answer 2

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

Question 3

what 4 major changes occur during inflammation and what are the cardinal signs of inflammation?

Answer 3

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

Question 4

what are inflammatory mediators?

Answer 4

• 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

Question 5

what is inflammatory mediators synthesis and redundancy?

Answer 5

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

Question 6

how do you alleviate inflammation? what are some effects of inflammation?

Answer 6

• 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

Question 7

inflammation inciting causes, beneficial outcomes and harmful outcomes?

Answer 7

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

Question 8

how do we reduce inflammation to reduce harmful outcomes?

Answer 8

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)

Question 9

What is the mechanism of action of aspirin? what are the main beneficial effects of NSAIDs?

Answer 9

• 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

Question 10

what is the synthesis of prostaglandins (PGs)?

Answer 10

• 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

Question 11

what will happen with respect ti prostaglandins in the absence of inflammatory stimulus?

Answer 11

• 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

Question 12

prostaglandins and inflammation in the presence of inflammatory stimulus

Answer 12

• 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

Question 13

NSAIDs mechanism of action

Answer 13

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

Question 14

what are the 3 locations where adverse effects of NSAIDs occur?

Answer 14

1. adverse effects in gastric mucosa
2. adverse effects in the kidney
3. adverse effects in platelets

Question 15

what is the mechanism of adverse effects of NSAIDs in gastric mucosa?

Answer 15

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)

Question 16

what is the mechanism of adverse effects of NSAIDs in the kidney?

Answer 16

• 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

Question 17

what is the mechanism of adverse effects of NSAIDs in platelets?

Answer 17

• 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)

Question 18

what are the PK properties and adverse effects of NSAIDs?

Answer 18

PK properties:
- weak acids: dissolve best in stomach (~100% absorption)
- primarily albumin-bound/accumulate in cells at site of inflammation
- hepatic phase II metabolism
- efficient renal excretion
- variable half-lives

adverse effects:
- GI ulceration and stomach bleeding
- inhibition of platelet aggregation → increased bleeding (most likely with aspirin)
- inhibition of uterine motility
- inhibition of PG-mediated renal perfusion; renal papillary necrosis in dehydrated patients

in humans, serious adverse effects occur at a rate of ~0.75 per million NSAID doses, and most are associated with overdosing

Question 19

what are additional adverse effects of NSAIDs due to inhibition of enzymes?

Answer 19

• NSAIDs are used to inhibit the inflammation caused by increased PG synthesis in damaged tissue, but unfortunately, PG synthesis in other tissues is also inhibited:
  Excessive inhibition of COX1 enzymes causes the main adverse effects of NSAIDs: gastric ulceration and bleeding
  1. Excessive inhibition of PG synthesis in GI epithelium
• ↓ PGI2 →↑ blood flow, ↑ acid secretion, ↓ bicarbonate secretion → gastric ulcers
• ↓ PGI2, ↓ gastris mucus → gastric ulcers
  2. excessive inhibition of PG synthesis in the kidney:
• ↓PG2, ↓ blood flow → hypoxia; renal papillary necrosis
  Note: that most PGs promote vasodilation in many tissues (PGF2 is the main exception, promoting vasoconstriction)

Question 20

what are the shared contraindications of NSAIDs?

Answer 20

• acute GI ulcer
• active or severe hepatic failure, renal failure, or congestive heart failure
• patients who are hypersensitive to ASA, salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics

Question 21

what is aspirin? (NSAIDs)

Answer 21

• acetylsalicylic acid
• inhibits COX1 and COX2
• inhibition is irreversible (acetylates the COX1 enzyme, destroying its activity)
• prolonged effects even at low doses
• anti-inflammatory, antipyretic, analgesic
• effective for fever, musculoskeletal and cutaneous pain, but poor for visceral (internal organ) pain
• aspirin inhibits COX1 in platelets for their entire lifetime (10 days) → reduced platelet aggregation

Question 22

what is ibuprofen? (NSAIDs)

Answer 22

• derivative of propionic acid
• inhibits both COX1 and COX2
• inhibition is reversible
• anti-inflammatory, analgesic, antipyretic
• indicated for arthritis, musculoskeletal pain, smooth muscle pain
• main adverse effect: gastric ulceration but less intense than with aspirin → preferred for some chronic uses (arthritis)

Question 23

what is celecoxib? (NSAIDs)

Answer 23

• almost 100% selective for COX2
• approved for osteoarthritis
• poor to negligible analgesia
• no effect on platelets/bleeding because COX2 not involved in thromboxane synthesis
• far less likely to cause GI ulceration and bleeding than non-selective NSAIDs if gastric lesions are not already present (COX2 products are involved in the healing of gastric ulcers)
• main concern with COX2 inhibition are reduced blood flow to kidneys and intravascular blood clotting
  -increased risk of stroke and myocardia infarction
• a concern with chronic use in patients with arthritis (osteoarthritis and rheumatoid arthritis), not with acute or intermittent use
• “chronic use of celebrex may cause an increased risk of serious adverse cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal”

Question 24

how do coxibs increase the risk of stroke and heart attack?

Answer 24

• 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

Question 25

what is acetaminophen?

Answer 25

- inhibits PG synthesis centrally (in CNS) → antipyretic, analgesic - little peripheral activity, so negligible anti-inflammatory effect and no effect on blood clotting - no longer considered an "NSAID"