nsaids

non-steroidal anti-inflammatory drugs (NSAIDs)

introduction

  • NSAIDs are a group of drugs which have anti-inflammatory and analgesic effects via their inhibitory action upon cyclooxygenase (COX) which is involved in the synthesis of prostaglandins.

precautions

  • NSAID use can be potentially fatal in high doses, prolonged used or in those at risk of their adverse effects, particularly, peptic ulceration/perforation and acute renal failure.
  • they should be avoided where possible in:
    • the elderly
    • PH peptic ulceration, alcohol abuse
    • hypertension
    • stroke/AMI risk
    • those who are hypovolaemic or dehydrated, particularly if they are also on ACE inhibitors
    • in addition, patients with asthma, nasal polyps or with past history of allergic reaction are at higher risk of having an life threatening acute allergic reaction
    • pregnancy
    • post-partum period in those who had pre-eclampsia or premature delivery
    • lactation
    • young children
    • renal impairment (CRN > 180umol/L)
    • coagulopathy
    • post-op for surgery with high risk of bleeding
    • PH Stevens-Johnson synd. or bullous / blistering rashes
    • suspected or confirmed intracranial bleeding
    • concurrent use of other NSAIDs
  • paracetamol (acetaminophen) is a much safer option in those with non-inflammatory pain (eg. mechanical pain due to osteoarthritis) as NSAIDs add little more benefit but expose the patient to much higher risks unnecessarily.

adverse effects

  • allergy and hypersensitivity reactions - bronchospasm is a particular concern
  • gastritis, peptic ulceration +/- perforation - rarely, this may occur even in previously well young adults within only a few days of Rx!
  • acute renal failure - particularly if dehydrated or on ACE inhibitors
  • nausea, diarrhoea, constipation
  • salt and water retention and worsening congestive cardiac failure
  • hypertension
  • regular use may cause hearing loss
  • photosensitivity and rashes
  • may also cause a number of other effects including raised LFTs, priapism, oesophagitis, etc - see full PI
  • COX-2 selective agents in particular, appear to increase the risk of thrombotic events such as stroke, and AMI
  • diclofenac may increase risk of Clostridium difficile by 35% 1)
  • aspirin also increases risk of bleeding such as epistaxis

pharmacologic effects:

PG Synthetase (cyclooxygenase (COX) ) inhibition:

  • There appears to be variability in this enzyme depending on the tissue, resulting in variable effects of NSAID's, but it may be possible to develop tissue-selective inhibitors;
  • Mechanism:
    • aspirin 40mg permanently acetylates the enzyme so that one dose is sufficient to block this enzyme for the life of a platelet (8-11days) as plat. cannot regenerate the enzyme;
      • NB. salicylate cannot acetylate the enzyme!
    • other agents competitively inhib. the enzyme:
      • NSAIDs & COX-2 inhibitors have analgesic & anti-inflammatory action via inhibition of COX-2 enzyme, this isoenzyme is massively up-regulated in inflammatory states such as RhA, so inhibiting it reduces inflammation.
      • paracetamol can only block the enzyme in environments free of peroxides & thus usually only in hypothalamus & is thus a poor antiinflammatory agent;
  • → decr. PGD2 → decr. all PG's & TX's
  • → decr. TXA2 → decr. 2nd phase of plat.aggreg.
  • COX-1 in platelets produces TXA2 which promotes platelet aggregation & vasoconstriction
  • COX-2 in endothelial cells produces prostacyclin (PGI2) which inhibits platelet aggregation & causes vasodilatation, thus COX-2 inhibitors could be predicted to increase risk of thrombosis and thus ischaemic stroke and AMI, as well as the usual NSAID adverse effects on increasing BP, exacerbating CCF, & impairing renal function.
  • COX-1 is the primary source of protective gastric mucosal PGs, hence the focus on COX-2 inhibitors to reduce the gastric toxicity associated with NSAIDs with the risk of serious upper GIT ulceration & bleeding reduced by 50-60% when using COX-2 inhibitors instead of NSAIDs.
  • in addition to analgesic, antipyretic & anti-inflammatory uses, COX-2 inhibitors may be of use in:
    • prophylaxis of colon cancer BUT risk of stroke & AMI outweighed the benefits

Non-selective NSAID's:

COX-2 preferential inhibitors:

  • meloxicam:
    • an enolcarboxamide related to piroxicam
    • 3-77x more selective for COX-2 than COX-1
    • slowly absorbed with tmax of 5-6hrs
    • half life 20hrs ⇒ once daily dosing
    • gastric injury as for placebo at 7.5mg/d but increases with higher doses
  • nimesulide:
    • introduced in 1985
    • extensively metabolised with half life of 1.6-5 hrs
    • analgesic, anti-inflammatory & anti-pyretic but similar gastric toxicity as other NSAIDs!
    • in 2/1/1999 Lancet, report of fatal fulminant hepatic failure in a woman taking this drug with temporal relationships suggesting causality

COX-2 selective inhibitors:

  • all increase risk of thrombotic events such as ischaemic stroke & AMI, thus should be used with care in at risk patients, preferably at lowest dose possible for short periods and with low dose aspirin or other anti-thrombotic Rx.
  • celecoxib:
    • 1,5 diaryl pyrazole-based compound
    • 375x more selective for COX-2 than COX-1 based on human recombinant enzyme assays
    • does not effect serum thromboxane or platelet function at usual doses up to 600mg bd
    • extensively metabolised with half life 11.2hrs
    • efficacy: 100-200mg bd equivalent to naproxen 500mg bd for osteoarthritis or RhA over 12wks
    • approved by US on 31/12/1998
    • dose:
      • RhA: 100mg bd (max. 800mg/d)
      • osteoarthritis: 200mg mane (max. 400mg/d)
      • analgesia: 100-400mg stat equal to aspirin for dental procedures
  • rofecoxib:
    • withdrawn from Australia in 2004 due to concerns of adverse effects such as stroke, AMI.
    • a methylsulphonylphenyl derivative
    • >800x more selective for COX-2 than COX-1
      • ⇒ even at 10-20x usual doses does not effect bleeding time nor cause gastric injury any more than placebo
    • long acting ⇒ once daily
  • parecoxib (Dynastat):
    • prodrug of valdecoxib
    • analgesia begins within 15 minutes of an intravenous or intramuscular injection and reaches a peak in two hours
    • extensively metabolised and most of the metabolites are excreted in the urine
    • may inhibit CYP2C19 and CYP2D6
    • 40 mg dose of parecoxib iv/im was significantly better than 20 mg
    • only approved for use as a single perioperative injection so most of the safety data refer to single doses.3)
  • etoricoxib (Arcoxia):
    • introduced in Australia in 2009
    • long acting ⇒ once daily
    • usual dose 60-120mg once daily (tablets are 30mg, 60mg, 120mg)
    • 120mg dose gives similar analgesia as:
      • 400mg ibuprofen or 550mg naproxen in Mx of dysmenorrhoea or dental pain.
      • 50mg tds indomethacin for acute gout
    • max. daily dose 120mg/d for maximum of 8 days.
    • C/I in severe renal or hepatic impairment
    • care with drugs which interact with NSAIDs.

history

  • Medicinal effects of barks of some plants incl. willow known to several cultures for centuries;
  • Rev.Edmund Stone (UK) used willow bark in fever of malaria;
  • Salicin the bitter glycoside active ingredient of willow bark isolated in 1829 by Leroux who also demonstrated its antipyretic effect.
  • Sodium salicylate derived from salicin 1st used in RhF & fevers 1875;
  • Acetylsalicylic acid introduced by Dresser in 1899 as aspirin (acetylsalicylic acid).
  • Acetanilide the parent member of para-aminophenol gp introduced into medicine in 1886 as antifebrin after its antipyretic activities accidentally discovered;
  • paracetamol (acetaminophen) 1st introduced 1887 & used in combination with other analgesics until realised in 1949 that it was the active metabolite of both acetanilide & phenacetin & thus gained popularity;
  • Aspirin clearly shown to be gastrotoxic in 1938.
  • Phenylbutazone the most important of the pyrazolone gp, introduced in 1949 but serum sickness/marrow suppression/hepatitis/nephritis;;
  • Other pyrazolones: antipyrine (phenazone), amidopyrine used 19thCent.
  • The fenamates' (mefenamic acid,etc) biological activities discovered in 1950's but did not gain widespread acceptance mainly due to diarrhoea.
  • No clear Rx advantage over other NSAID's but used in 1° dysmenorrhoea;
  • Indomethacin was the 1st of allied NSAID's to be widely used - introduced 1963 then sulindac & since then many more have been synthesised;
  • Tolmetin introduced in 1976 (US) as better tolerated than aspirin;
  • Propionic acid derivatives (ibuprofen, naproxen) are usually better tolerated than aspirin or indomethacin;
  • Piroxicam (Feldene) an oxicam derivative
  • Diclofenac (Voltaren) the 1st of the phenylacetic acid derivative as NSAID;
  • COX-2 gene discovered in 1990-91.
  • Ketorolac trometamol (Toradol) introduced 1992 (Aust) as periph. acting PG synthetase inhibitor developed specially for its analgesic properties as a 30mg IM replacement for pethidine 50-100mg or morphine 6-12mg IM;
  • In 1996-98, some existing NSAIDs shown to be COX-2 preferential (meloxicam, nimesulide)
  • New drugs designed to be COX-2 “selective”:
    • celecoxib (approved in US 31/12/1998)
    • rofecoxib (likely to be approved in US in 1999)
  • 2003, reports of hypertensive crises & deaths when NSAIDs given in post partum period to women with PH pre-eclampsia or premature delivery. Advised to carefully watch BP in such pts if must use NSAIDs
  • 2004: Vioxx (rofecoxib) withdrawn as long term Rx shown to increase risk of thrombotic events such as AMI and stroke. TGA places new restrictions on COX-2 inhibitors in Australia including avoidance in patients with high risk of cardiovascular events such as PH AMI, and the maximal long term dose of Celebrex (celecoxib) reduced to 200mg/d for other patients.
  • 2005: Pfizer believes that the restrictions to Celebrex should apply to all NSAIDs not just COX-2 inhibitors.
  • 2012: diclofenac reported to increase risk of Clostridium difficile by 35% 4)
nsaids.txt · Last modified: 2012/12/18 06:43 by gary1