Aspirin

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rINN: Aspirin
Other Names
acetylsalicylic acid, 2-(acetyloxy)benzoic acid, 2-acetyloxybenzoic acid, 2-acetoxybenzoic acid, acetylsalicylate, Aspro ®, etc etc
Pharmacological Information
Pharmacology Images
Aspirin molecule
AspirinStructure.png
Web information on Aspirin
Metabolism & Interactions
Aspirin inhibits the excretion of uric acid.
Mechanism of Action
  • irreversible COX (cyclooxygenase) inhibition.
  • uncouples oxidative phosphorylation in mitochondria
  • induces the formation of NO-radicals
Other Issues for Aspirin
  • By acetylation produces complete inhibition of platelet aggregation until new enzymes made, of the order of 72 hours.
  • The analgesic and antipyretic actions last for only a short time, of the order of 3-4 hours
  • The potential of interaction with the reversible inhibitors of COX has lead to a lot of fun and games still not resolved
Relevant Clinical Literature
UK Guidance
Regulatory Literature
Other Literature
Other Wikis
Wikipedia on Aspirin (Less technical, ? quality control)

Contents


Introduction

The second prototype synthetic drug after diamorphine, it was marketed by Bayer first in 1899 and helped found the modern pharmaceutical industry because of its effectiveness and safety profile. It remains one of the most widely used medications, but should not be used in its original indication in children any more as there are safer alternatives. It was a component of the proposed PolyPill as it is such a cheap and effective medicine in its antiplatelet indications. Willow bark was noted in 1763 to be anti-pyretic and analgesic. The drug is derived from salicylate, the active principle in the Willow (Salix) bark. However it is rarely used for its original indications now and even as of 2018 optimal dosing and use is likely to be poorly understood by doctors who do not keep up with advances in clinical knowledge.

The benefits of the willow family were known to Hippocrates but also to African Hottentots and North American Indians [1]

The first salicylate (salicin) was isolated from Philipendula ulmaria (part of the Spiraea genus as is the willow family) during a search for an alternative to quinine. It was an effective analgesic but caused too much dyspepsia for clinical use. The German pharmaceutical firm Bayer developed an acetyl compound of salicin, acetyl salicylic acid and marketed it as Aspirin from the genus name (acetyl + spiraea). It was also noted to have antipyretic properties [2] During the first World War the allies ignored all German patents and aspirin was widely copied. At the end of the war Bayer failed to win the patent back and the name has been with us ever since. It has been over used, for example in primary prevention and to try to reduce recurrent miscarriage. The use of low dose aspirin in older adults directed towards primary prevention of cardiovascular disease results in no benefit and a higher risk of major haemorrhage.


Clinical Use

Indications

  • Secondary prophylaxis against further ischaemic events after atherosclerotic ischaemic cardiovascular or cerebrovascular presentations.
  • Pain relief
  • Rheumatic fever
  • Prevention of colorectal cancer in high risk populations[3] (may be out of license)
  • Reduction in distant adenocarcinoma metastasis[4](may be out of license, in colorectal cancer there is preliminary evidence that almost all the benefit is confined to those with a PIK3CA gene mutation[5])

Administration

Oral, but rectal and intravenous preparations are available.

Dose

In original anti-inflammatory indications for an adult it was say 300mg four times a day. In a 70kg adult the efficacy of low dose aspirin, which is any dose less than 300mg resulted in standard doses of less than 100mg a day. However obese adults more typically need 150mg a day for optimal antiplatelet action.

Clinical Issues

Where it does not work

  • Unexplained recurrent miscarriages[6]
  • Primary prevention of cardiovascular disease[7].

Hearts and Brains vs Stomachs

A small dose of Aspirin reduces the risk of first or subsequent MI, death from MI and of ischaemic stroke. Any dose of aspirin increases the risk of bleeding, chiefly gastrointestinal haemorrhage. All these risks increase with age and all have a cloud of other risk factors and modifiers. In secondary prevention it is beneficial after any atherosclerotic ischaemic cardiovascular or cerebrovascular presentation[8][9].

The benefits appear varied between the sexes, with meta-analysis of 6 trials, mainly in secondary prevention, in about 100 000 people suggesting aspirin reduces stroke in women (by 17%) and MI in men (by 32%). The risk of bleeding, may also be sex dependent - 72% and 68% increased in women and men respectively[10]. The evidence has accumulated that aspirin is unlikely to be benefical in all primary prevention scenarios[11]. It is also is unlikely to be benefical in secondary prevention after a presentation with peripheral vascular disease not needing procedural intervention[12].


Prevention of Cancer

The evidence for colorectal cancer prevention is now very strong[3] and may well be strong enough to justify primary prevention in high risk groups, but there is also evidence suggestive that several solid cancers, particularly adenocarcinomas may decrease with long term use[13]:

Aspirin Resistance

A small proportion of people seem resistant to Aspirin, and a larger proportion have new cardiovascular events while a prescription for aspirin is active. Reasons for the latter include the former, a lack of concordance IE not taking the tablets, interference from (other) NSAIDs including OTC analgesics, and that the treatment is no more perfect than are most.

Resistance could at least in theory be determined or even screened for by measuring either platelet function or levels of thromboxane A2 hoping to find that either is severely depressed. At present this is more available in research units than a practical investigation.

Increasing the dose of aspirin seems to overcome resistance to a degree in vitro, but not in vivo.

Aspirin and NSAIDs

Unhappily it appears that combining low dose aspirin and some NSAIDs does in real life lead to loss of effectiveness of low dose aspirin. This issue which has been known on theoretical grounds since the early 1980's[14] was subject to an FDA warning on combining ibuprofen and aspirin in 2006 but more evidence has accumulated since. In a 27-month period, 72% of a cohort of stroke patients on aspirin who also took either ibuprofen or naproxen had a recurrent ischaemic episode. The same paper[15] confirmed a significant reduction in the magnitude and duration of aspirin's inhibitory effect on platelet aggregation when ibuprofen was given. Further ibuprofen, indomethacin, naproxen, and tiaprofenic acid all block the antiplatelet effect of aspirin, although diclofenac, rofecoxib[16] sulindac and celecoxib[17] appear not to.

This issue is potentially important because many doctors and patients are likely to be unaware of an evidence base that has steadily accumulated and there can be good clinical reasons why the combination might be considered.

Toxicity

Contra-indications

Cautions and Interactions

Side effects

Commoner important
  • Upper gastro-intestinal. All NSAIDs are associated with serious gastrointestinal side effects. For non-selective NSAIDs these were most common with azapropazone and least common with Ibuprofen. Selective cyclo-oxygenase-2 inhibitors are associated with a lower risk of gastrointestinal side effects. However this effect is negated if the coxib is given with low dose aspirin. It is now known that in primary prevention low dose aspirin has no net benefit in normal western populations due to the incidence of serious bleeding side effects approaching that of vascular events prevented[18]. Only male diabetics may be an exception if the goal is to prevent myocardial infarction[19]. Gastroprotection with low dose aspirin should be considered where patients are at high risk of gastrointestinal bleeding. For example those older than 75 years and those also taking anticoagulants appear to have good absolute benefit from co-prescription of a proton pump inhibitor if the aim is to prevent upper G/I bleeding. Showing reduction in mortality with such co-prescription is more difficult but the case has been made on population economic grounds and such co-prescription is likely to be under used due to it not being necessary in most of the patients recruited to the original large scale intervention trials.
  • Renal failure (especially in combination with diuretics and drugs acting on angiotensin system). In elderly patients renal function with low dose aspirin decreases by about 19%[20] and this is worse if patients already on a diuretic[21]. There is a dose related effect with patients already on an ACE inhibitor but this is more marked at doses of 160mg and above[22]. Aspirin chronic use has long been known to be associated with chronic renal failure that can be modelled on a lifetime accumulated dose model[23]. The risk of overt chronic renal failure in secondary prevention is about 10 times less than the number of myocardial infarctions prevented in the same time period however !
  • Fluid retention
Rarer Important
  • Cardiovascular events. This may be related to degree of cyclo-oxygenase-2 inhibition
  • Asthma
  • Gout -Low dose aspirin blocks renal excretion of urate, typically by about 17%[20]. The patient with an acute flare of gout and their physician can have different perceptions as to the importance of this issue.
List of NSAID side-effects - many rare

Some NSAIDs are more likely to cause these side-effects than others but they all appear to be class side-effects. Aspirin certainly can cause many of them at full treatment doses, as well as tinnitus ++

Special advice

Pharmacology

References

  1. http://books.google.com/books?id=htGD3Y7WNxwC&pg=PA503&lpg=PA503&dq=aspirin+salix+spiraea&source=web&ots=ViN2zj4cJR&sig=OAX50Apdk0OZk1lewc5KYr5k8gU&hl=en&sa=X&oi=book_result&resnum=4&ct=result Accessed 21 January 2009
  2. http://www.botgard.ucla.edu/html/botanytextbooks/economicbotany/Salix Oh willow, don't weep. Accessed 21 January 2009
  3. a b Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, Meade TW. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010 Nov 20; 376(9754):1741-50.(Link to article – subscription may be required.)
  4. Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012 Mar 20.(Epub ahead of print) (Link to article – subscription may be required.)
  5. Liao X, Lockhead P, Nishihara R et al. Aspirin use, tumour PIK3CA mutation, and colorectal-cancer survival N Eng J Med 2012;367:1596-606 DOI:10.1056/NEJMoa1207756
  6. Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyák K, Mol BW, Folkeringa N, Nahuis M, Papatsonis DN, Büller HR, van der Veen F, Middeldorp S. Aspirin plus Heparin or Aspirin Alone in Women with Recurrent Miscarriage. The New England journal of medicine. 2010 Mar 24.(Epub ahead of print) (Link to article – subscription may be required.)
  7. Barnett H, Burrill P, Iheanacho I. Don't use aspirin for primary prevention of cardiovascular disease. BMJ (Clinical research ed.). 2010; 340:c1805.(Epub)
  8. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ (Clinical research ed.). 2002 Jan 12; 324(7329):71-86.
  9. Keller TT, Squizzato A, Middeldorp S. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease. Cochrane database of systematic reviews (Online). 2007; (3):CD005158.(Epub) (Link to article – subscription may be required.)
  10. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA : the journal of the American Medical Association. 2006 Jan 18; 295(3):306-13.(Link to article – subscription may be required.)
  11. Wolff T, Miller T, Ko S. Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force. Annals of internal medicine. 2009 Mar 17; 150(6):405-10.
  12. Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA : the journal of the American Medical Association. 2009 May 13; 301(18):1909-19.(Link to article – subscription may be required.)
  13. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2010 Dec 6.(Epub ahead of print) (Link to article – subscription may be required.)
  14. Rao GH, Johnson GG, Reddy KR, White JG. Ibuprofen protects platelet cyclooxygenase from irreversible inhibition by aspirin. Arteriosclerosis (Dallas, Tex.). 1983 Jul-Aug; 3(4):383-8.
  15. Gengo FM, Rubin L, Robson M, Rainka M, Gengo MF, Mager DE, Bates V. Effects of ibuprofen on the magnitude and duration of aspirin's inhibition of platelet aggregation: clinical consequences in stroke prophylaxis. Journal of clinical pharmacology. 2008 Jan; 48(1):117-22.(Link to article – subscription may be required.)
  16. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. The New England journal of medicine. 2001 Dec 20; 345(25):1809-17.(Link to article – subscription may be required.)
  17. Gladding PA, Webster MW, Farrell HB, Zeng IS, Park R, Ruijne N. The antiplatelet effect of six non-steroidal anti-inflammatory drugs and their pharmacodynamic interaction with aspirin in healthy volunteers. The American journal of cardiology. 2008 Apr 1; 101(7):1060-3.(Link to article – subscription may be required.)
  18. Aspirin for primary prevention of cardiovascular disease? Drug and therapeutics bulletin. 2009 Nov; 47(11):122-5.(Link to article – subscription may be required.)
  19. De Berardis G, Sacco M, Strippoli GF, Pellegrini F, Graziano G, Tognoni G, Nicolucci A. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ (Clinical research ed.). 2009; 339:b4531.(Epub)
  20. a b Segal R, Lubart E, Leibovitz A, Iaina A, Caspi D. Renal effects of low dose aspirin in elderly patients. The Israel Medical Association journal : IMAJ. 2006 Oct; 8(10):679-82.
  21. Sweileh WM. Potential adverse effects of a low-dose aspirin-diuretic combination on kidney function. International journal of clinical pharmacology and therapeutics. 2007 Nov; 45(11):601-5.
  22. Juhlin T, Jönsson BA, Höglund P. Renal effects of aspirin are clearly dose-dependent and are of clinical importance from a dose of 160 mg. European journal of heart failure : journal of the Working Group on Heart Failure of the European Society of Cardiology. 2008 Sep; 10(9):892-8.(Link to article – subscription may be required.)
  23. Fored CM, Ejerblad E, Lindblad P, Fryzek JP, Dickman PW, Signorello LB, Lipworth L, Elinder CG, Blot WJ, McLaughlin JK, Zack MM, Nyrén O. Acetaminophen, aspirin, and chronic renal failure. The New England journal of medicine. 2001 Dec 20; 345(25):1801-8.(Link to article – subscription may be required.)