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Physiology & Science: Therapeutics > Non-steroidal anti-inflammatory drugs > Flashcards

Non-steroidal anti-inflammatory drugs Flashcards

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1
Q

Give an example of an archetypal NSAID

A

Aspirin

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2
Q

What are 3 characteristics of NSAIDs?

A
  • Analgesic (prevention of pain)
  • Anti-pyretic (lowering of raised temp/fever)
  • Anti-inflammatory (decrease an immune response)
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3
Q

Hence, what are NSAIDs used to treat?

A
  • 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

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4
Q

What is the main mechanism of therapeutic action of NSAIDs and how does aspirin work differently to other NSAIDs?

A
  • 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
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5
Q

What is meant by ‘super aspirins’?

A

Newer COX-2 selective agents

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6
Q

Why is paracetamol not an NSAID and how does it work?

A
  • 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
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7
Q

Name other NSAIDs apart from aspirin

A
  • etodolac
  • meloxicam
  • ibuprofen
  • naproxen
  • indomethacin
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8
Q

Describe the mechanism for onset of fever

A
  • 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
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9
Q

How are NSAIDs antipyretic?

A
  • NSAIDs block PGE2 production
  • Set point therefore lowered back to normal value
  • Fever dissipates
  • NSAIDs have no effect on normal body temperature
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10
Q

How do prostaglandins bring about pain (hyperalgesia)?

A
  • 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
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11
Q

How are NSAIDs analgesic?

A
  • 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
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12
Q

How are PGE2 and PGI2 inflammatory?

A

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
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13
Q

How are NSAIDs anti-inflammatory?

A
  • 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
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14
Q

What is the role of TXA2 in vascular haemostasis (within CVS)?

A
  • Platelet aggregation
  • Vasoconstriction
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15
Q

How do NSAIDs impact on TXA2 in the CVS and how can this be problematic?

A
  • 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
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16
Q

Which vascular endothelial mediators help to bring about haemostatic balance in opposition to TXA2?

A
  • TXA2 = platelet aggregator
  • PGI2/E2 and NO = prevent platelet aggregation + promote vasodilation
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17
Q

What happens when the endothelium is damaged (haemostasis)?

A
  • Damaged endothelium
  • Increase collagen
  • Increase vWF
  • Platelets adhere + release TXA2 -> inc platelet aggregation
  • Decreased blood loss
  • Fibrin formation (traps microbes + facilitates phagocytosis)
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18
Q

What can inappropriate platelet aggregation lead to?

A

Thrombus + ischaemic heart disease

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19
Q

How is aspirin beneficial in cardiovascular disorders?

A

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

20
Q

How do prostaglandins impact on the skeletal system and how do NSAIDs help this?

A

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

21
Q

What system side effects are the most common adverse reactions to older NSAIDs?

A

Gastric effects

22
Q

What is the importance of PGs within the GI tract and what effect do NSAIDs have therefore?

A

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.

23
Q

NSAIDs are said to be acidic, therefore what (consequences) can they cause within the GI tract?

A
  • 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)
24
Q

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

A
  • 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

25
Q

What effect do COX-2 selective agents have on TXA2 and PGI2?

A
  • No effect on TXA2 in platelets (as that is COX-1)
  • But decrease PGI2 in blood vessels
26
Q

Why can’t you give a patient an NSAID and a COX-2 inhibitor?

A
  • Will cause an ULCER
  • eg. Diclofenac (NSAID) - selective for COX-2, but inhibits COX-1 in GIT —> ulcers (ensure you eat before taking this)
27
Q

What is the link between NSAIDs and pyrexia (fever)?

A
  • NSAIDs inhibit pyrexia
  • In overdose NSAIDs produce paradoxical hyperpyrexia, stupor + coma -> increase metabolism + metabolic acid production
28
Q

Why should NSAIDs never be used in children with influenza or chicken pox?

A

Pose a Reye’s Syndrome risk (brain + liver damage)

29
Q

What is dysmenorrhoea?

A

Low anterior pelvic pain associated with periods

30
Q

How are NSAIDs beneficial to women (genital tract)? Which particular NSAID?

A
  • 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
31
Q

What effect do PGs have on the kidney?

A
  • Vasodilator PGs (E2/I2) regulate renal blood flow
  • PGI2 mediates renin release
  • PGE2 decreases Na+ reabsorption
  • Both also increase GFR
32
Q

How do NSAIDs therefore impact in the kidney and what are consequences of this?

A
  • 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
33
Q

What effects do PGs have on the resp tract?

A
  • PGs (PGD2, PGF2a) have both constrictor + dilator effects on airway smooth muscle
34
Q

NSAIDs have no effect on normal airway tone, but when must NSAIDs be avoided or used with caution?

A
  • Asthma
  • 20% asthma patients wheeze when given aspirin or other NSAIDs bc they are hypersensitive to these drugs
35
Q

What is the effect of aspirin/NSAIDs at toxic doses in regards to respiration?

A
  • Initially stimulates respiration
  • Actions on respiratory centre + uncoupling of oxidative phosphorylation - medulla stimulated
  • Resp alkalosis caused by hyperventilation (-> CO2 washout from lungs)
36
Q

How might NSAIDs help to achieve closure of a patent ductus arteriosus and when should NSAIDs not be given in this case?

A
  • 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
37
Q

Apart from those mentioned, what are other indications of NSAIDs where they are useful for certain conditions and pathologies?

A
  • 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
38
Q

What is ulcerative collitis and what causes it?

A
  • Inflammation of the bowel
  • Caused by increased PGs (-> inflammation)
39
Q

What are the aims of drug treatment for ulcerative colitis?

A
  • 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
40
Q

What is the mechanism of action of sulfasalazine?

A
  • 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
41
Q

What are side effects of sulfasalazine?

A
  • Indigestion, feeling or being sick, abdo pain, diarrhoea
  • Dizziness, headache, difficulty sleeping, tinnitus
  • Coughing; itchy rash, may affect taste + cause sore mouth
42
Q

What is gout?

A
  • 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
43
Q

What drugs are used to treat gout?

A
  • NSAIDs that are anti-gout
  • eg. naproxen, diclofenac, indomethacin
44
Q

What is the mode of action of naproxen?

A
  • 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)
45
Q

What are side-effects of naproxen?

A
  • 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)

Physiology & Science: Therapeutics (6 decks)

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