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nsaids [2020/02/22 10:22] (current)
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 +====== non-steroidal anti-inflammatory drugs (NSAIDs) ======
 +see also [[eicosanoids]],​ [[analgesics]],​ [[ODsalicylates|salicylate poisoning]],​ [[aspirin]],​ [[colchicine]]
 +  *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.
 +  *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**
 +    ***[[ccf]]**
 +    *hypertension
 +    *stroke/AMI risk
 +    *those who are **hypovolaemic** or **dehydrated**,​ particularly if they are also on **[[ACEIs]]**
 +    *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 [[rash_bullous]]
 +    *suspected or confirmed intracranial bleeding
 +    *concurrent use of other NSAIDs
 +  *[[paracetamol]] 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]] - 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 [[ACEIs]]
 +  *nausea, diarrhoea, constipation
 +  *salt and water retention and worsening [[CCF]]
 +  *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% (([[http://​​doi/​10.1111/​j.1365-2125.2012.04191.x/​abstract|British Journal of Clinical Pharmacology 2012]]))
 +  *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:​ =====
 +  *[[aspirin|acetylsalicylic acid (aspirin)]]
 +    *additional anti-platelet activity
 +  *[[diclofenac]] (Voltaren)
 +    *may increase risk of [[clostridium_difficile]] by 35% (([[http://​​doi/​10.1111/​j.1365-2125.2012.04191.x/​abstract|British Journal of Clinical Pharmacology 2012]]))
 +  *[[indomethacin]] (Indocid)
 +    *usual adult dose 25-50mg tds o or 100mg rectal suppository bd
 +  *[[ibuprofen]] (Brufen, Nurofen)
 +    *usual adult dose 400mg tds
 +    *at daily doses up to 1200mg is said to have less adverse GIT effects than the other non-selective NSAIDs ​
 +  *[[ketorolac]]
 +  *[[mefenamic acid]] (Ponstan)
 +    *used mainly in Rx of [[dysmenorrhoea]] but tends to cause diarrhoea
 +  *[[naproxen]] (Naprosyn/​Naprogesic)
 +  *piroxicam (Feldene)
 +=====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.(([[http://​​magazine/​25/​4/​94/​9/​new-drugs-401/​parecoxib|Aust. Prescriber 2002]]))
 +  ***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]].
 +  *Acetanilide the parent member of para-aminophenol gp introduced into medicine in 1886 as antifebrin after its antipyretic activities accidentally discovered;
 +  *[[Paracetamol]] 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% (([[http://​​doi/​10.1111/​j.1365-2125.2012.04191.x/​abstract|British Journal of Clinical Pharmacology 2012]]))
nsaids.txt · Last modified: 2020/02/22 10:22 (external edit)