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Flashcards in Rheumatology - NSAIDs Deck (19)
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What enzyme do NSAIDs inhibit?

NSAIDs are a diverse group of drugs but they all work by inhibiting the enzyme cyclo-oxygenase (COX). COX converts arachidonic acid into endoperoxides as part of the eicosinoid system.

This system produces prostaglandins, thromboxanes, and prostacyclin (as well as leukotrienes) from phosphalipids in response to stimuli (usually tissue injury). A stimulus upregulates phospholipase A2 which converts phospholipids into arachidonic acid and starts the pathway off.


Does COX exist in different forms?

COX exists in 2 forms:
- COX - 1 which is the constitutively active tissue isoform
- COX - 2 which is the inducible form stimulated by cytokines at sites of inflammation

Inhibition of COX prevents prostaglandin synthesis which is largely responsible for the therapeutic effect of NSAIDs. But inhibiting prostaglandins causes damage to the gastric mucosa (causing dyspepsia, nausea and gastritis).

Inhibition of COX-2 is thought to produce the therapeutic effect of NSAIDs, while inhibition of COX-1 produces GI toxicity. Most NSAIDs are somewhat selective for COX-1.


What is a major problem with selective COX-2 inhibitors?

Selective COX-2 inhibitors include celecoxib, etoricoxib and lumiracoxib. They have a similar efficacy to non-selective COX inhibitors but the incidence of GI perforation, obstruction and bleeding is reduced by at least 50%. But they do not provide any cardioprotection and are associated with an increased incidence of MI.


How do NSAIDS produce their analgesic effect?

The analgesic effect of NSAIDs occurs centrally and peripherally, but the peripheral effects predominate. The analgesic action is associated with their anti-inflammatory effect and results from decreased prostaglandin synthesis at the site of inflammation.

Prostaglandins produce very little pain by themselves but enhance the nociceptive effect of other pain causing mediators (e.g. histamine, bradykinin).


Why are NSAIDs anti-inflammatory?

The role of prostaglandins in inflammation is to produce vasodilation and increased vascular permeability. However, inhibition of prostaglandin synthesis by NSAIDS attenuates, rather than stops inflammation because it has no effect on other mediators (such as cytokines).

Despite this, they can help with stiffness, swelling and pain symptoms that occur in many MSK diseases.


How do NSAIDs produce an anti-pyretic effect?

During a fever, pyrogens such as interleukin 1 is released from leucocytes and acts directly on the thermoregulatory centre of the hypothalamus to increase body temperature. The effect is associated with a rise in brain prostaglandins (which are pyrogenic). NSAIDs (especially aspirin and paracetamol) prevent the temperature raising effects on IL-1 by preventing the rise in brain prostaglandin levels.


How do non-selective COX inhibitors work?

COX - 1 and COX - 2 have a long channel that is wider in COX - 2 enzymes. Non-selective NSAIDs enter the channels in both enzymes and, except for aspirin, block them by binding to hydrogen bonds to an arginine residue. This reversibly inhibits the enzymes by preventing the access of arachidonic acid.


Why is aspirin a unique non - selective NSAID?

Most non-selective NSAIDs are reversible. Aspirin acetylates an amino acid residue within the COX channel and is therefore irreversible.


Why is aspirin not used for treatment of inflammatory joint disease?

50% of patients could not tolerate the adverse side effects of aspirin (nausea, vomiting, epigastric pain, tinnitus) caused by the high doses of soluble aspirin necessary to achieve its anti-inflammatory effect. Because the propionic acid derivatives (e.g. ibuprofen, naproxen) are associated with fewer side effects, these are often tried first.


Why is low dose aspirin given after an MI?

Low dose aspirin inhibits the enzyme thromboxane synthase which converts endoperoxides into thromboxane A2 primarily on platelets. It also inhibits prostacyclin synthase present on endothelial cells that produces prostacyclin.

Thromboxane A2 causes platelet aggregation and vasoconstriction. Prostacyclin causes platelet disaggregation and vasodilation.

Platelets have no nucleus, and cannot re-synthesise thromboxane A2 once aspirin has irreversibly inhibited it. However, endothelial cells can produce more prostacyclin synthase and therefore more prostacyclin. This causes vasodilation which increases oxygen supply and reduces clot formation.


Is paracetamol and NSAID? Why is it better used for non inflammatory pain?

Paracetamol has no anti-inflammatory effect and works by reducing cytoplasmic peroxide tone. Peroxide is necessary to activate a haem enzyme. In areas of acute inflammation, paracetamol is not very effective because neutrophils and monocytes produce high levels of hydrogen peroxide and lipid peroxide which overcome the actions of the drug.

However, paracetamol is an effective analgesic in conditions in which leucocyte infiltration is absent or low.


What are the adverse effects of NSAIDs?

Adverse effects are common because NSAIDs are usually given long term and at high doses. They are also widely used in elderly patients who are more susceptible.

1) GI disturbances
2) Nephrotoxicity
3) Bronchospasm (especially in asthmatics)
4) skin rashes and other allergies
5) Cardiovascular side effects (primarily COX-2 inhibitors)


Why do NSAIDs cause GI toxicity?

In the stomach COX - 1 produces prostaglandins that stimulate mucus and bicarbonate secretion and cause vasodilation which protects the gastric mucosa. Non-selective NSAIDs inhibit COX-1 and because they reduce the cytoprotective effect of prostaglandins they frequently cause serious upper GI side effects including bleeding and ulceration. PPI's are widely used to avoid upper GI toxicity but this does not prevent blood loss from the small bowel, which is a significant cause of anaemia in patients on non selective NSAIDs.

The newer COX-2 selective NSAIDs - e.g. celecoxib are associated with much lower GI toxicity but have a much higher risk of MI presumably because they do not inhibit aggregation of platelets (which contain COX-1).

Misoprostol is a PGEi derivative that is effective in preventing GI toxicity of NSAIDs. It is mainly used for patients with a history of peptic ulcer disease whose need for NSAID treatment is such that analgesia cannot be withdrawn.


Why do NSAIDs cause renal damage?

Prostaglandins are powerful vasodilators synthesised in the renal medulla and glomerulus. They maintain GFR by dilating the afferent arteriole and inhibition of prostaglandin synthesis may result in sodium retention, reduced renal blood flow and renal failure.

This is especially a problem for patients on vasoconstrictor catecholamines and ACE inhibitors (e.g. CCF, cirrhosis). NSAIDs may cause interstitial nephritis and hyperkalaemia. Prolonged analgesic abuse over a number of years can cause renal papillary necrosis and chronic renal failure.


What are the "safest" NSAIDs?

The propionic acid derivatives such as ibuprofen, fenbufen and naproxen are widely regarded as the drugs of first choice for treatment of inflammatory joint disease because they are associated with the lowest incidence of adverse side effects.


Diclofenac, Indometacin, Piroxicam

Diclofenac - actions similar to naproxen, can be given by IV or IM injection to prevent or treat post op pain.

Indometacin - one of the more effective agents but has a higher incidence of adverse side effects including ulceration, gastric bleeding, headaches, and dizziness. It can also cause blood dyscrasias.

Piroxicam - long half life requiring once daily doses, high incidence of GI bleeding in the elderly.


What is used to treat acute attacks of gout?

Acute attacks of gout are treated with diclofenac, indometacin or other NSAIDs but NOT aspirin. This is because aspirin raises plasma urate levels at low doses by inhibiting uric acid secretion in the renal tubules.


What is colchicine and when is it used?

Colchicine is effective in acute gout. It binds to tubulin in leucocytes and prevents its polymerisation into microtubules. This inhibits phagocytic activity and migration of leukocytes to the areas of uric acid deposition and hence reduces the inflammatory response. But colchicine causes nausea, vomiting, diarrhoea and abdominal pain.


What agents are used for prophylactic treatment of gout?

Allopurinol lowers plasma urate by inhibiting xanthine oxidase, the enzyme responsible for converting xanthine to uric acid. It is useful in patients with recurrent gout.

Uricosuric drugs, such as probenecid, inhibit renal tubular reabsorption of uric acid, increasing its excretion. Plenty of water should be taken to prevent crystallisation of urate in the urine. These drugs are less effective and more toxic than allopurinol and are normally reserved for patients that cannot tolerate allopurinol.