Non-steroidal anti-inflammatory drugs Flashcards
Give an example of an archetypal NSAID
Aspirin
What are 3 characteristics of NSAIDs?
- Analgesic (prevention of pain)
- Anti-pyretic (lowering of raised temp/fever)
- Anti-inflammatory (decrease an immune response)
Hence, what are NSAIDs used to treat?
- Low grade pain (chronic inflammation, eg. arthritis)
- Bone pain (cancer metastases)
- Fever (associated w/ infections)
- Inflammation (decrease symptoms - oedema, redness, itch)
Responses are dependent on inhibitory profiles on different COXs
What is the main mechanism of therapeutic action of NSAIDs and how does aspirin work differently to other NSAIDs?
- Inhibition of COX
- COX converts AA to PGs + TXs
- COX-1 - constitutively active, platelets
- COX-2 - inducible enzyme eg. by IL-1b + TNFa
- Inhibition of COX-2 reduces PGs/TXs inflammatory agents
- Aspirin acts irreversibly on (both) COX; others act reversibly and this is significant in its use as a prophylactic in cardiovascular disease
- Older generation NSAIDs inhibit both COX-1 + COX-2
What is meant by ‘super aspirins’?
Newer COX-2 selective agents
Why is paracetamol not an NSAID and how does it work?
- Analgesic w/o anti-inflammatory effects
- Little inhibition of COX-1 or 2 in peripheral tissue
- Weakly inhibits COX-3 in CNS - doesn’t expl all of its effects
- Modulates serotonergic neurotransmission (?)
- Inhibits COX-mediated generation of hydroxypeptides from AA
- Hydroxypeptides stimulate COX activity
Name other NSAIDs apart from aspirin
- etodolac
- meloxicam
- ibuprofen
- naproxen
- indomethacin
Describe the mechanism for onset of fever
- bacterial endotoxins produced during infections
- stimulate macrophages to release IL-1
- IL-1B acts on hypothalamus to cause PGE2 release (via COX2)
- PGE2 depresses temperature sensitive neurones
- PGE2 elevates set point temperature -> onset of fever
How are NSAIDs antipyretic?
- NSAIDs block PGE2 production
- Set point therefore lowered back to normal value
- Fever dissipates
- NSAIDs have no effect on normal body temperature
How do prostaglandins bring about pain (hyperalgesia)?
- PGs sensitise and stimulate nociceptors
- Oedema prod by inflammation -> activates nociceptors too
- PGs interact synergistically w other pain prod substances (kinins, 5HT, histamine) to produce hyperalgesia
How are NSAIDs analgesic?
- NSAIDs block PG production -> breaks cycle + leads to pain relief
- Useful for pain associated with production of inflammatory agents (PGs/TXs)
- eg. arthritis, toothache, headache (as NSAIDs inhibit PG-mediated vasodilatation)
- COX-1, COX-2 and COX-3 inhibiton in CNS
How are PGE2 and PGI2 inflammatory?
Have powerful acute inflammatory effects
- Arteriolar dilatation (inc blood flow)
- Inc permeability in post-capillary venules
- Both processes increase influx of inflammatory mediators into interstitial space
How are NSAIDs anti-inflammatory?
- Inhibition of PGE2 and PGI2 -> reduces redness + swelling
- NSAIDs provide only ‘symptomatic relief’
- don’t cure underlying causes of inflammation
- eg. help but do not cure arthritis
- Decrease COX-2 generated PGs; effects develop gradually
What is the role of TXA2 in vascular haemostasis (within CVS)?
- Platelet aggregation
- Vasoconstriction
How do NSAIDs impact on TXA2 in the CVS and how can this be problematic?
- NSAIDs decrease TXA2 (COX-1 product) levels
- So increase bleeding time
- Problematic in surgery / childbirth
- Where platelet aggregation is inc in disease, aspirin has a role in prophylactic treatment
Which vascular endothelial mediators help to bring about haemostatic balance in opposition to TXA2?
- TXA2 = platelet aggregator
- PGI2/E2 and NO = prevent platelet aggregation + promote vasodilation
What happens when the endothelium is damaged (haemostasis)?
- Damaged endothelium
- Increase collagen
- Increase vWF
- Platelets adhere + release TXA2 -> inc platelet aggregation
- Decreased blood loss
- Fibrin formation (traps microbes + facilitates phagocytosis)
What can inappropriate platelet aggregation lead to?
Thrombus + ischaemic heart disease
How is aspirin beneficial in cardiovascular disorders?
You have 2 enzymes making 2 different products w/ 2 diff functions:
- Endothelial cell via (inducible) COX-2 –> PGI2 (anti-aggregatory vasodilator)
- Platelet via (constitutively active) COX-1 –> TXA2 (pro-aggregatory vasoconstrictor)
Low doses of aspirin will block BOTH of these pathways, so no effect right? But OVER TIME… the endothelial cell COX-2 recovers, whereas platelet COX-1 cannot recover -> PGI/E2 is continued to be made, therefore aspirin has a net anti-aggregatory vasodilator effect
How do prostaglandins impact on the skeletal system and how do NSAIDs help this?
PGs with acute inflammatory effects contribute to swelling + pain in arthritis (joint pains)
- Arteriolar dilation
- Inc microvascular permeability
- Hyperalgesia - inc sensitivity to pain
NSAIDs thus diminish these effects but do not treat the cause
What system side effects are the most common adverse reactions to older NSAIDs?
Gastric effects
What is the importance of PGs within the GI tract and what effect do NSAIDs have therefore?
PGE2/I2 important in protecting gastric mucosa:
- stimulate mucus + HCO3- secretion
- inhibit gastric acid secretion
NSAIDs decrease these cytoprotective mechanisms causing bleeding + ulceration. COX-2 selective inhibitors may be ‘gastric-friendly’, as it is suggested that COX-1 is expressed in the gut.
NSAIDs are said to be acidic, therefore what (consequences) can they cause within the GI tract?
- Decrease mucus + HCO3<strong>-</strong> secretion
- Increase acid secretion
- Increase LT production (LOX pathway not affected)
- Increase blood loss
- Interfere with tissue healing (COX-2 inhibition)
- Nausea, dyspepsia, GI contraction (COX-1 inhibition)
COX-2 selective agents are said to be less effective analgesics due to less inhibition of COX-3 in the brain and spinal cord. Give examples of COX-2 selective agents
- Etoricoxib - most selective COX-2 inhibitor
- Rofecoxib - withdrawn due to CV effects
- Celecoxib
- Valdecoxib
Some not suitable for RA/OA; use meloxicam, etodolac etc. instead
What effect do COX-2 selective agents have on TXA2 and PGI2?
- No effect on TXA2 in platelets (as that is COX-1)
- But decrease PGI2 in blood vessels
Why can’t you give a patient an NSAID and a COX-2 inhibitor?
- Will cause an ULCER
- eg. Diclofenac (NSAID) - selective for COX-2, but inhibits COX-1 in GIT —> ulcers (ensure you eat before taking this)
What is the link between NSAIDs and pyrexia (fever)?
- NSAIDs inhibit pyrexia
- In overdose NSAIDs produce paradoxical hyperpyrexia, stupor + coma -> increase metabolism + metabolic acid production
Why should NSAIDs never be used in children with influenza or chicken pox?
Pose a Reye’s Syndrome risk (brain + liver damage)
What is dysmenorrhoea?
Low anterior pelvic pain associated with periods
How are NSAIDs beneficial to women (genital tract)? Which particular NSAID?
- PGs cause pain + sm muscle spasm during menstruation
- NSAIDs used as treatment
- Mefenamic acid (an NSAID) reduces blood loss
- NSAIDs may be useful in primary dysmenrrhoea
- PGs (PGE2 + PGF2a) - important in uterine contractions in childbirth, thus NSAIDs delay contractions
- Many NSAIDs increase post partum blood loss bc TXA2 prod prevented
- NSAIDs delay and retard labour
What effect do PGs have on the kidney?
- Vasodilator PGs (E2/I2) regulate renal blood flow
- PGI2 mediates renin release
- PGE2 decreases Na+ reabsorption
- Both also increase GFR
How do NSAIDs therefore impact in the kidney and what are consequences of this?
- NSAIDs thus reduce renal blood flow (+ inc BP)
- Chronic renal injury may result
- Effectiveness of some antihypertensive drugs is reduced by concurrent treatment w/ NSAIDs
- Inhibition of COX-2 decreases sodium excretion + increases intravascular volume
- Average BP rise = 2/3mmhg but varies
- Low dose aspirin doesn’t seem to interfere with antihypertensive therapy but regular use should be avoided
What effects do PGs have on the resp tract?
- PGs (PGD2, PGF2a) have both constrictor + dilator effects on airway smooth muscle
NSAIDs have no effect on normal airway tone, but when must NSAIDs be avoided or used with caution?
- Asthma
- 20% asthma patients wheeze when given aspirin or other NSAIDs bc they are hypersensitive to these drugs
What is the effect of aspirin/NSAIDs at toxic doses in regards to respiration?
- Initially stimulates respiration
- Actions on respiratory centre + uncoupling of oxidative phosphorylation - medulla stimulated
- Resp alkalosis caused by hyperventilation (-> CO2 washout from lungs)
How might NSAIDs help to achieve closure of a patent ductus arteriosus and when should NSAIDs not be given in this case?
- Patency may be inappropriately maintained by PGE2 and PGI2
- Indomethacin + ibuporofen are useful
- Alprostadil infusion
- Sometimes may close by age 1 (or surgical closure)
- Symptoms: low birth weight, SoB, sweating, tiring easily
- Do not give NSAIDs in 3rd trimester to avoid premature closure of ductus
Apart from those mentioned, what are other indications of NSAIDs where they are useful for certain conditions and pathologies?
- Decrease colonic polyps + prevent colon cancer
- May decrease Alzheimer’s risk
- Post-op pain relief
- Renal colic - upper part of abo pain/groin usually caused by kidney stones
What is ulcerative collitis and what causes it?
- Inflammation of the bowel
- Caused by increased PGs (-> inflammation)
What are the aims of drug treatment for ulcerative colitis?
- Reduce symptoms AKA induce remission
- Maintain remission
- First line treatment options: aminosalicylates (sulfasalazine + mesalazine)
- Decrease inflammation for mild-mod ulcerative colitis
- Short-term treatment of flare-ups
- Useful in long term to maintain remission
What is the mechanism of action of sulfasalazine?
- Metabolised to 5-aminosalicyclic acid (5-ASA) and sulfapyridine
- Reduces synthesis of eicosanoids
- By blocking activity of COX + LOX
- COX + LOX activities are high in ulcerative collitis
What are side effects of sulfasalazine?
- Indigestion, feeling or being sick, abdo pain, diarrhoea
- Dizziness, headache, difficulty sleeping, tinnitus
- Coughing; itchy rash, may affect taste + cause sore mouth
What is gout?
- Type of arthritis
- Accumulation of uric acid crystals in joints
- Painful inflammation caused by build up of uric acid
- Uric acid is in blood + harmless at low levels
- Uric acid prevents damage to blood vessel linings
- Passed out with urine + faeces
- High levels of uric acid in blood cause tiny grit-like crystals to collect in joints which irritate joint tissues, causing inflammation + pain
What drugs are used to treat gout?
- NSAIDs that are anti-gout
- eg. naproxen, diclofenac, indomethacin
What is the mode of action of naproxen?
- Inhibits COX1/COX2 levels
- Lowers PG levels
- Targets mediators engaged at onset of inflammation
- Exhibits analgesic, anti-inflammatory + antipyretic activity
- Inhibits platelet aggregation (inhibits platelet TXA2)
What are side-effects of naproxen?
- Dizziness
- Nausea, diarrhoea
- Indigestion
- Blurred vision
- Abnormal LFT
- Water retention
- Ringing in the ears
- Hives
Relatively risk neutral for CV events (heart attacks are rare)
