NSAIDs

what is inflammation

the active response of tissues to injury that can be either protective & beneficial or exaggerated & harmful

local response at the site of injury '

complex response 

inflammation is a complex response which involves

• immune response

• coagulation cascade

• regeneration & repair processes

function of inflammation

to protect the body following injury

• removal of injurious stimuli (bacteria, chemical irritants, etc)

• removal of necrotic cells

• containment of damage (e.g. abcessation)

• stimulation of repair & regeneration

what are the 4 major changes that occur in inflammation

1) blood vessels dilate (warmth & redness)

2) blood vessels become leaky (fluid & proteins enter tissue → edema)

3) WBCs enter inflamed tissue

4) Nociceptors become sensitized (pain)

cardinal signs of inflammation

1. heat

2. redness

3. swelling

4. pain

5. loss of function

upon tissue injury/infection, leukocytes rapidly produce ___________ that effect changes on blood vessels and tissues

inflammatory mediators

eicosanoids are (mostly) pro-inflammatory mediators:

1. prostaglandins

2. thromboxane

3. prostacylin

4. leukotrienes

what do the most effective anti-inflammatory drugs inhibit

many or all of the pro-inflammatory mediators

synthesis or inflammatory mediators

• some are produced in advance for rapid release at time of insult or injury

• e.g. histamine exists pre-formed inside cells

how are eicosanoids synthesized

at the site of tissue injury in response to the injury to trigger the inflammatory response and recruit immune cells

redundancy?

several mediators will trigger the same inflammatory process, so inhibitors of one class of mediator may lessen, but not abolish, inflammation

in many cases, ___________ will alleviate the inflammation

eliminating the insult

in some cases, an exaggerated inflammatory reaction to a mild or harmless stimulus does more harm than good

e.g. allergies, autoimmune reactions, etc

chronic inflammation stimulates

fibrosis (scarring)

depending on the site, may impair

vision, motility, oxygenation, or cause seizures, arrhythmias, intestinal strictures, etc

anti-inflammatory therapy may be necessary if

stimulus cannot be identified or eliminated

inflammation summary

non-pharmacological options to reduce inflammation

• ice & heat 

• elevate

• lifestyle habits

pharmacological options to reduce inflammation

NSAIDs

glucocorticoids

aspirin MoA

inhibition of prostaglandin synthesis

what is the oldest NSAID

aspirin

what are NSAIDs

a family of chemically dissimilar drugs that produce three main benefits

three main benefits that NSAIDs produce

• anti-inflammatory effects

• antipyretic effects (fever)

• analgesic effects

clinical uses of NSAIDs

for the relief of musculoskeletal & inflammatory pain, including post-operative pain

what are prostaglandins

PGs are eicosanoids that exhibit diverse roles in inflammation and cellular signalling

what does phospholipase A release upon stimulation

arachidonic acid from the plasma membrane

what enzymes then synthesize PGs and other eicosanoids from arachidonic acid

Cyclo-oxygenase (COX) enzymes

what two main COX enzymes exist in humans

COX-1 and COX-2

in the absence of inflammatory stimulus, COX-1

is a normal ‘housekeeping’ enzyme present at low levels in most tissues

in the absence of inflammatory stimulus, COX-2 is

normally present at much lower levels in most tissues, but is important for homeostasis in a few tissues (e.g. renal medulla, gastric mucosa)

thromboxane

synthesized by COX1 in platelets

promotion of platelet aggregation

other PGs (PGD2. PGE2)

maintenance of tissue blood flow

many other tissue-specific protective functions

prostacyclin (PGI2)

inhibition of platelet aggregation

vasodilation

other protective functions

PGE2 and PGI2 also involved in

gastric mucosa protection:

decrease acid secretion by gastric parietal cells, increase bicarb & mucus secretion, increase vasodilation

in the presence of inflammatory stimulus

COX-2 is upregulated in response 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 what

inflammation

• redness

• swelling 

• heat 

• pain

• loss of function

COX-1: constitutively expressed

always expressed, this enzyme consistently makes thromboxane and other prostaglandins required for normal maintenance, regardless or inflammation status

COX-2 inducibly expressed

• this enzyme is only expressed at high levels to produce more prostaglandins and prostacyclin when inflammation is present

most NSAIDs inhibit

both COX1 & COX2

NSAIDs mechanism of action

NSAIDs inhibit cyclooxygenase enzymes

most NSAIDs inhibit both COX1 and COX2, what does this do

• reduces synthesis of PGs, including those that promote vasodilation 

• reduces blood flow to site 

• reduces sensitization or nociceptors

• alleviates inflammation

major benefit of NSAIDs is

a reduction in blood flow to the site of injury

adverse effects of NSAIDs

• adverse effects in gastric mucosa

• adverse effects in the kidney

• adverse effects on platelets

adverse effects in gastric mucosa

the normal protective effects of PGs in the stomach are inhibited, resulting in

• decreased blood flow, bicarb secretion, & mucus secretion

• increased acid secretion

This can cause gastric bleeding with or without ulceration (the most common adverse effect associated with NSAIDs)

adverse effects in the kidney

• COX enzymes produce PGs that maintain adequate blood flow to many tissues, including the renal medulla

• excessive COX inhibition can lead to renal medullary hypoxia & papillary necorsis

• in contrast to other tissues, in which COX-1 is the main homeostatic cyclooxygenase, COX-2 is particularly important in maintaining adequate blood flow in the renal medulla

adverse effects on platelets

• only COX1 is present in platelets 

• NSAIDs inhibit the conversion of AA to thromboxane in platelets

• result is a slightly increased general tendency to bleed

• excessive doses of NSAIDs can cause more pronounced bleeding

  (this effect can be used in our advanatage, e.g. low dose aspirin is used chronically in humans ro reduce myocardial infarction and stroke risk by inhibiting platelet aggregation)

mechanism of adverse effects in GI epitelium

1. excessive inhibition of PG synthesis in GI epithelium

• decrease PGI2 → decrease blood flow → increase acid secretion, decrease bicarbonate secretion → gastric ulcers

• decreased PGE2, decreased gastric mucus → gastric ulcers

mechanism of adverse effects in the kidney

1. excessive inhibition of PG synthesis in the kidney 

• decreased PGE2, decreased blood flow → hypoxia; renal papillary necrosis

mechanism of adverse effects in platelets

1. increased bleeding 

• decreased TXA2, decreased platelet aggregation → less clotting, increased bleeding

NSAIDs share similar

PK properties, adverse effects, and contraindications

PK properties

• weak acids; dissolve best in stomach (~100% absorption) 

• primarily albumin bound/accumulate in cells at site of infection 

• extensive hepatic metabolism 

• efficient renal excretion 

• variable half-lifes (<6 hours: ibuprofen; >10 hours: naproxen)

adverse effects of NSAIDs

• GI ulceration and stomach bleeding 

• inhibition of platelet aggregation → increased bleeding (most likely with aspirin) 

• inhibition of PG-mediated renal perfusion; renal papillary necrosis in dehydrated pts 

• inhibition of uterine motility 

in humans, serious adverse events occur at rate of

~0.75 per million NSAID doses, and most are associated with overdosing

contraindications of NSAIDs

• pts who are hypersensitive to ASA, salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), analgesic, antipyretics 

• acute gastrointestinal ulcer

• history of gastrointestinal ulcer

• hemmorhagic diasthesis 

• active or severe hepatic failure, renal failure, or congestive heart failure

• pts with a history of asthma induced by the administration of salicylates or substances with a similar action 

• combination with methotrexate at doses of 15mg/weel or more

• late trimester of pregnancy

aspirin

• acetylsalicylic acid

MoA of aspirin

• Inhibits COX-1 and COX-2

is the inhibition of COX-1 and COX-2 reversible?

irreversible

(acetylates the COX 1 enzyme, destroying its activity)

are the effects long lasting

prolonged effects even at low doses

effects of aspirin

anti-inflammatory, antipyretic, analgesic

what is aspirin effective for

fever, musculoskeletal and cutaneous pain, but poor for visceral (internal organ) pain

what does aspirin do

inhibits COX-1 in platelets for their entire lifetime (10 days) → reduced platelet aggregation

Ibuprofen

derivative of propionic acid

what does ibuprofen do

inhibits both COX-1 and COX-2

is inhibition reversible

inhibition is reversible

effects of aspirin

anti-inflammatory, analgesic, antipyretic

when is advil recommended

• arthritis, musculoskeletal pain, smooth muscle pain (maybe)

main adverse effect of ibuprofen

• gastric ulceration but less intense than with aspirin → preferred for some chronic uses (arthritis)

celecoxib

almost 100% effective for COX-2

Celecoxib is approved for

osteoarthritis

does it provide analgesia

poor to negligible analgesia

does celecoxib effect platelets

no effect on platelets/bleeding because COX-2 not involved in thromboxane synthesis

is celecoxib likely to cause GI ulceration

• far less likely to cause GI ulceration & bleeding than non-selective NSAIDs (if gastric lesions are not already present (COX2 products are involved in the healing of gastric ulcers)

main concerns with COX-2 inhibition

• reduced blood flow to kidneys and intravascular blood clotting

• increased risk of stroke & myocardial infarction 

• a concern with chronic use in patients with arthritis (osteoarthritis and rheumatoid arthritis), not with acute or intermittent use 

how do Coxibs increase the risk of stroke and heart attack

regular non-selective NSAIDs inhibit the synthesis of all COX-1 and -2 products, both pro-and anti- clotting. Thromboxane is a potent pro-clotting molecule (promotes platelet aggregation), and its inhibition produces a greater effect than the inhibition of prostacyclin, so the net effect is slightly in favour of bleeding 

Coxibs inhibit only COX-2, so less PGI2 is produced than usual, but thromboxane synthesis is not inhibited. 

this tips the balance in favour of intravascular coagulation and therefore, stroke and myocardial infarction.

these effects are only observed after prolonged (>18 months) use

Acetaminophen

• inhibits PG synthesis centrally (in CNS) → antipyretic, analgesic

• little peripheral activity, so negligible anti-inflammatory effect & no effect on blood clotting 

• no longer considered an NSAID