Week 10 SAIDs and Inflammation Flashcards
Innate immune system activation = inflammation
Innate immune cells recognise and are activated by molecular patterns associated with injury (ischaemia, trauma) or infection
- Cellular damage (cell contents): - e.g. K+, DNA, H+, ATP, warning proteins
= (DAMPs)
and / or - Pathogen (non-self)
components, e.g.
- viral proteins,
- bacteria cell wall
=> PAMPs
Innate immune system definition and purpose
a “non-specific” first line body defence response to cell injury or infection
purpose:
- localise and eliminate the injurious agent
- remove damaged tissue components
- body can begin to heal
5 cardinal signs of inflammation
redness
heat
swelling
pain
decreased function
(systemic = fever)
Acute inflammation (2 phases)
- Vascular phase
- cellular phase
Vascular phase
1.Injured cells, sensory neurons & resident immune cells release chemical mediator
2. Chemical mediators induce vasodilation (warmth) & increase capillary permeability => influx of plasma proteins that propagate inflammation (swelling, redness)
3. Plasma proteins lead to blood clotting, complement system and kinin production
4. The ‘complement system’ plus inflammatory mediators (chemokines) attract phagocytic white blood cells (e.g. monocytes and neutrophils) to the injury site =>
Cellular phase
Neutrophils & macrophages enter infl. tissue through the leaky blood capillaries
Phagocytic cells :
- ingest invading pathogens, dead cells and cellular debris
- release cytokines (enhance inflamm.) & ‘pyrogens’ & induce fever.
Chronic inflammation
Inflammation that lasts for 2 weeks or more.
*Results from an inability of the inflammatory response to remove the cause of inflammation
*Eg. chronic inflammatory diseases include
- arthritis (osteo / rheumatoid),
- Crohn’s disease & IBD
- asthma / COPD
- tuberculosis
*Can be dominated by lymphocytes & monocytes/macrophages
*Persistent inflammation causes local tissue damage and high fibroblast activity at the site causes local deposition of fibrin and formation of ‘fibrotic’ (dead/ cell-free) tissue (scarring)
inflammatory
mediators
eicosanoids = (Greek for “20” as derived from C20 fatty acids) arachidonic acid metabolites, including prostaglandins (PGs) and leukotrienes (LTs), thromboxane
- histamine = stored in mast cells (the major role of histamine in inflammation is to mediate allergic reactions)
- platelet activating factor (PAF) and C5a
Except for histamine, inflammatory mediators are not stored; they are synthesized and released in response to inflammatory stimuli, thus inflammation takes time.
What is the inflammatory synthetic process?
Inflammatory stimulus
->
Arachidonic acid - esterified to membrane phospholipids
->
[phopholipase A2]
->
free cytosolic Arachidonic Acid
=
Prostanoids: PGs, prostacyclin (PGI2),
thromboxanes.
Inflammatory mediator overview
Products of cyclooxygenase (COX) enzymes: prostaglandins (PGs), prostacyclin (PGI2)
COX = cyclo-oxygenase enzyme
LOX = lipoxygenase enzyme
CYP = cytochrome P450
PG = prostaglandin
LT = leukotriene
EET = epoxyeicosatrienoic acid
HETE = hydroxyeicosatetraenoic acid
Prostaglandins (PGs)
Inflammatary roles:
- vasodilation
- altered platelet function
- hyperalgesia (abnormally increased sensitivity to pain)
- bronchoconstriction
- uterine contraction
- fever
How do prostanoids bring about their effects?
- G-protein coupled receptors (GPCRs), Table 33-1;
- Great diversity in receptor structures and G-protein interactions.
- e.g. PGE2, PGI2 and PGD2 each cause local vasodilation and reduced BP; PGF2a causes constriction of pulmonary arteries and veins, no change in BP.
- These effects may differ by tissue, e.g. contraction of GI and uterine smooth muscle, increased gastric secretions.
Endogenous agents which reduce PLA2 activity
Endogenous corticosteroids are made in the adrenal cortex:
* Mineralocorticoids are involved in water and electrolyte balance (aldosterone);
* Glucocorticoids have widespread effects on
metabolism, as well as mechanisms of
defense (hydrocortisone (“aka” cortisol)).
Exogenous glucocorticoids are most commonly used for their anti-inflammatory effects, hopefully with reduced mineralocorticoid activity
– very lipophilic.
- Common drugs used are hydrocortisone, prednisolone, and dexamethasone.
SAIDs
Glucocorticosteroids
Steroid hormones
e.g. Prednisolone - synthetic GCS
Hydrocortisone - endogenous GCS
Physiological role
= glucose homeostasis under stress
SAIDs reduce inflammation, but also have strong immunosuppressive and wider effects on the body
=> most potent anti-inflammatories BUT many side effects
Main anti-inflammatory mechanisms:
- increase synthesis of anti inflammatory proteins
- decrease synthesis of pro-inflammatory mediators
Main anti-inflammatory mechanism of action of SAIDs
Lipocortin-1 inhibits phospholipase A2
AND
Reduces the expression of COX enzymes
Overall result is the reduced production of prostaglandins + a lot more.
SAIDs (corticosteroids): Summary
- Bind to intracellular glucocorticoid receptors in cytoplasm
- enter the cell nucleus, alter inflammatory gene expression
- SAIDs upregulate anti-inflammatory genes e.g. IL-10, b2-adrenoceptor,
lipocortin-1 (annexin) (inhibits prostaglandin synthesis) - Inhibit pro-inflammatory pathways : synthesis and release (cytokines, chemokines, enzymes e.g. < iNOS, < COX2 … )
- Decrease inflammatory cell number (proliferation) = allergies
- Inhibition of IL2 & Th cell
proliferation = immunosuppression
Anti-inflammatory Indications of corticosteroids
- Transplant rejection (in combination with other immunosuppressants)
- Rheumatoid arthritis (injected into joints)
- Inflammatory bowel disease / Crohn’s disease / Ulcerative colitis
- Psoriasis & Systemic lupus erythematosus
- Asthma / allergies
- Septic shock… (can restore cardiac output and increase BP)
Potential side effects of corticosteroids
Immunosuppressive activity increases risk of microbial infections.
- Worsen diabetes (promote hyperglycaemia by lowering glucose uptake and promoting gluconeogenesis)
- Some drugs can activate mineralocorticoid receptor and thus cause Na+ and water retention, leading to hypertension and heart failure.
- May increase the risk of peptic ulcers (greater gastric acid, less gut protection)
- May increase osteoporosis, as Ca2+ absorption is decreased and vit D is blocked,
NSAIDs
Non-Steroidal Anti-Inflammatory Drugs
NSAIDs inhibit prostaglandin synthesis by inhibiting COX-1 & 2
- All* NSAIDs have the following
effects, - Anti-inflammatory*
– Anti-pyretic (lower body temp)
– Analgesic (reduce pain) magnitude of these effects vary for each drug and pain indication - NSAIDs provide relief from
- swelling in arthritis,
- bone fractures,
- soft tissue injury,
- postoperative & dental pain,
- menstrual pain,
- headaches and migraines.
- Used extensively to control mild pain and inflammation
- NSAIDs are the most prescribed medications in the world
- Use of NSAIDs is on the rise due to:
– availability without a prescription
– use of aspirin for prevention of thrombotic disorders
– the ageing population
COX enzymes
COX-1: produces protective prostaglandins that :
* Coat the stomach lining with mucus (=protection), PGE2
* Aid in platelet aggregation (prevent
excessive bleeding), TXA
* Regulate renal blood flow
* Induce parturition, PGF + PGE2
COX 2: produces inflammatory
prostaglandins that:
- sensitise skin nociceptors
- increase body temperature by acting on the hypothalamus
- recruit inflammatory cells
towards injured parts of the body
Antipyretic effects of NSAIDs
- Body temperature controlled by
a hypothalamic “thermostat” which ensures that heat production and heat loss are in balance around a set-point. - Fever occurs when hypothalamic
interleukin-1 (IL-1), an inflammatory mediator, stimulates production of PGE2 that elevates the set-point. - In the POAH, neurons with PGE
receptors change the firing rate of
neurons in the febrile response,
raising the set-point. - NSAIDs act by interrupting this
synthesis of PGE2, returning the
set-point to normal temperature. - The body then adjusts dilation of
blood vessels, sweating, etc. to
restore normal body temperature.
Antithrombotic effects
At low concentrations of aspirin
PERMANENTLY acetylate blood platelet COX-1 enzyme, leading to inactivation of thromboxane production.
- Thromboxane is a vasoconstrictor and aids in platelet aggregation. By
inactivating it, there is a marked
reduction in blood clotting. - Platelets are cell fragments without
a nucleus- so cannot replace COX-1
once acetylated. It may take a week
for the platelets to be regenerated.
Aspirin thus prolongs clotting time of the blood; a single dose of aspirin doubles clotting time.
Side effects common to most NSAIDs
(mainly due to inhibition of COX1?)
- Gastrointestinal disturbances:
– Inhibition of gastric mucosal production by PGs
– Blockage of the ‘acid secreting inhibitory’ effects of PGs
=> Due to systemic exposure to NSAIDs, NOT gastric exposure
– Direct irritation of the gastric mucosa may contribute - Renal effects:
– Reduce renal blood flow, increase toxic effects of drugs
=> Inhibition of PG/prostacyclin production that maintains high renal blood flow - Cardiovascular effects:
– anticoagulant effects of some NSAIDs can prolong bleeding time - Uncommon effects:
– Skin reactions: idiosyncratic rashes, erythematosus and photosensitivity
Severity of side effects correlates to effectiveness as an anti-inflammatory
Aspirin
(Class: salicylates)
Irreversibly inhibits COX 1 & 2 through COX acetylation (COX1:COX2 ratio is >10:1)
Effects on pain and fever:
– decreases hyperalgesia after tissue injury => analgesic
– Anti-inflammatory in arthritis
– PGs in the hypothalamus change the ‘set point’ for body temp
– Aspirin ‘resets’ the body’s internal thermostat to normal => decreases fever.
Effects on blood clotting: (antiplatelet activity)
* Inhibits platelet thromboxane synthesis – slows clotting
* Single 0.5 g dose doubles clotting time for ~5 days
* Don’t use 1 week before surgery
(risk of operative and post-operative bleeding)
* Used to prevent arterial clotting in at risk patients (elderly)
* Limited effect on venous clotting (DVT)
Aspirin: Major side effects
GASTIC IRRITATION
The major side effect of NSAIDs!
Can cause gastric ulceration
BLOOD CLOTTING
Risk of internal or excessive bleeding
NEPHROTOXICITY
Slows renal blood flow and urine flow
PREGNANCY
Can delay labour (stop taking aspirin in late pregnancy)
CNS EFFECTS
* Tinnitus
* Confusion
* Delirium
* Convulsions
* Coma
REYE’S SYNDROME
* In children with viral illnesses (eg. flu)
* Fatty degeneration of liver & kidneys
* Swelling of the brain
* Can be fatal
* Contraindicated in <12 year olds
& <20 with viral fever
Naproxen
(Class: propionic acids)
Competitive, reversible inhibitor of COX 1 & 2 (2 fold more selective for COX 1) (longer half life than ibuprofen)
Effects on pain and fever:
* More anti-inflammatory effect than aspirin
* Same thermoregulatory effect as aspirin
* More effective against menstrual pain than other NSAIDs (works
better if taken BEFORE menstrual pain sets in)
* Longer lasting pain relief against menstrual pain than ibuprofen
* Can be used to treat headaches, arthritis etc as with ibuprofen,
but more commonly used to treat menstrual pain
Adverse effects:
* Does not have the same effects on blood clotting as aspirin, can INCREASE risk of thrombosis
* Some gastric irritation can occur, but less severe than aspirin
* Better tolerated than other NSAIDs (but more adverse effect on the liver than ibuprofen)
Indomethacin
(Class: indolacetic acid)
Competitive, reversible inhibitor of COX 1 & 2 (7 fold more selective for COX 1)
Effects on pain and fever:
* Most potent anti-inflammatory effect of all of the NSAIDs
* 10-fold more effective analgesic effect than aspirin
* Better anti-pyretic effect than aspirin
* Generally only administered for gout and arthritis because of its toxicity
Adverse effects:
* Causes more significant GI toxicity than any other NSAID
* Causes more significant cardiovascular side effects than any other NSAID
* Contraindicated in children <14 years old and during pregnancy
Diclofenac
(Class: fenamate)
Competitive, reversible inhibitor of COX 1 & 2 (COX2 > COX 1)
Effects on pain and fever:
* One of the most potent NSAIDs since it is believed to also inhibit
lipoxygenase and phospholipase A2 which are also involved in the
synthesis of PGs
* Significantly more potent analgesic effects than aspirin and indomethacin
* Longest lasting analgesic effect of any NSAID (6-8h)
* Generally only used to treat chronic inflammatory conditions/pain
* Can be applied topically as a gel (eg. Voltaren)
Adverse effects:
* Increased risk of cardiovascular disease over other NSAIDs (because of increased potency against COX2)
* risk of GI disturbances (major side effect of diclofenac, 20% patients)
* Risk of acute liver damage
* Hypersensitivity reactions from topical application
Ibuprofen
(Class: propionic acids)
Competitive, reversible inhibitor of COX 1 & 2
More potent for COX 2
Effects on pain and fever:
* More anti-inflammatory effect than aspirin
* Same thermoregulatory (<fever) effect as aspirin
* More effective against menstrual pain than other NSAIDs (works better if taken BEFORE menstrual pain sets in)
* Commonly used to treat rheumatoid arthritis (effective in 50% of patients) and other forms of pain (where paracetamol has limited effectiveness)
Adverse effects:
* Does not have the same effects on blood clotting as aspirin and can INCREASE risk of thrombosis
* Some gastric irritation can occur, but less severe than aspirin
* Better tolerated than other NSAIDs
* Safe for use in children
Celecoxib
COX-2 specific inhibitor
Uses:
– Treatment of rheumatoid and osteo-arthritis
– Patients where traditional NSAIDs are contraindicated due to GI disturbances
Adverse effects: several ‘coxibs’ withdrawn from the market
- Selective COX-2 inhibitors are good in theory, but the following side effects are still seen:
– Cardiovascular problems (increased risk of heart attack and stroke)
– Increased risk of gastrointestinal bleeding (mechanism is believed to be due to the role of COX-2 in healing gastric ulcers, so by inhibiting COX-2
you may get slower healing and increased bleeding break-through)
Why is celecoxib having these CV effects?
- COX-2 function in the vasculature is to produce prostacyclin (PGI2) which is antithrombotic and a potent vasodilator. Inhibition of COX-2 reduces PGI2 leading to potential platelet aggregation and vasoconstriction.
- Constitutively expressed COX-2 in the kidney plays key roles in mediation of renin release, regulation of Na excretion and regulation of renal blood flow. Inhibition of COX-2 reduces PGI2 and PGE2, which results in hypertension and oedema as arterial pressure homeostasis is disrupted. :(
- In addition to these “coxibs”, several traditional NSAIDs exhibit selectivity for COX-2, and may have similar CV risks.
Paracetamol
Acetaminophen
Not a traditional NSAID
Believed to be selective for COX-3 in the CNS
Effects on pain and fever:
* Weak anti-inflammatory effect
(unlike conventional NSAIDs)
* Good analgesic effect (for mild pain, e.g. headaches)
* Very strong anti-pyretic effect (better for fever than traditional NSAIDs)
* Most well tolerated analgesic drug
* suitable substitute for aspirin for antipyretic and analgesic effects esp. in patients for whom aspirin is
contraindicated (GIT problems)
Adverse effects:
* No adverse gastric effects
* No effect on bleeding time and no cardiovascular toxicity
* Major toxic effects are in the liver. Highly hepatotoxic when overdosed due to metabolism in the liver.
Toxicity
-there is a dose-dependent, hepatic necrosis which can be fatal, as well as renal necrosis
-chronic use can lead to irreversible
nephrotoxicity in some people
-hepatoxicity occurs with 10 gm dose
-fatal dose around 20-30 gms
Hepatotoxicity
-due to formation of toxic reactive intermediary
-hepatic damage signs appear in 2-4 days
-liver enzymes and bilirubin levels in plasma rise
-1-2 % of untreated patients will die of liver failure
