Tag: aspirin

Aspirin for prevention of preeclampsia

Non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated in the third trimester of pregnancy because of the risk of premature closure of the ductus arteriosus. So why is aspirin used to prevent preeclampsia?

Low-dose aspirin is used to prevent preeclampsia in women at high risk of developing preeclampsia. However, NSAIDs are known to promote closure of the ductus arteriosus (see Cyclooxygenase inhibitors for closure of the ductus arteriosus) and so are contraindicated in the third trimester of pregnancy.  So why is aspirin used to prevent preeclampsia?

Preeclampsia is associated with increased platelet turnover and increases in platelet-derived thromboxane levels. Low doses of aspirin once per day are sufficient to be antiplatelet and reduce thromboxane production by the platelets. Such low doses are unlikely likely to trigger closure of the ductus arteriousus and so are relatively safe even in the third trimester of pregnancy. Thus, for the women at high risk of preeclampsia the risk-to-benefit ratio is in favour of prescribing low-dose aspirin.

Additionally, it has been reported that preeclampsia is associated with exaggerated inflammatory responses. The anti-inflammatory actions of aspirin may therefore also be beneficial in preventing preeclampsia, although the low doses used would not produce a strong anti-inflammatory effect.

There remains debate over the optimal dose and the best time to start aspirin treatment. Typically, doses between 75 mg and 162 mg/day have been used started typically before 12 weeks of gestation and certainly before 16 weeks.

Reference:

August, P & Jeyabalan, A (2019) Preeclampsia: Prevention. Lockwood, CJ & Barss, VA ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on February 19, 2019).

Why is aspirin not used in gout?

Non-steroidal anti-inflammatory drugs (NSAIDs)  are used to control pain and inflammation in gout. Aspirin is the prototypical NSAID and is available over-the-counter (i.e. without a doctor’s prescription or consultation with a pharmacist or prescribing nurse). So why are patients with gout told not to take aspirin? 

Gout is caused by elevated uric acid levels. At high levels, uric acid is deposited as monosodium urate crystals in the tissues of the joints.  When the body’s immune system attacks the monosodium urate crystals, it triggers severe bouts of pain and inflammation.  During these acute gouty attacks, the priority in the treatment of gout is to reduce the pain and inflammation. NSAIDs can help to achieve this.  Between gouty attacks, a key aim in the treatment of gout is to reduce the plasma levels of uric acid to prevent recurrence of acute gouty attacks.  This can be achieved by dietary modifications together with drugs such as allopurinol, which inhibits uric acid synthesis, and uricosuric drugs, which increase uric acid excretion through the kidney.

Aspirin is both an NSAID and uricosuric at high doses. Therefore, it might at first seem reasonable to use aspirin for the treatment of gout. However, the story is more complicated. At lower doses, aspirin and other salicylates are in fact anti-uricosuric. Taking aspirin or other salicylates can increase plasma uric acid levels and increase the risk of gout.  Aspirin and other salicylates can also interfere with the action of uricosuric drugs prescribed for the treatment of gout.

So, what about taking high doses of aspirin? No, that is not helpful either.

Firstly, the uricosuric effect of apsirin only manifests at or above the higher end of the normal analgesic and anti-inflammatory therapeutic dosage range. Meanwhile, aspirin has a very short half-life of only about 20 min. This is the reason why for analgesic and anti-inflammatory use you have to take aspirin once every 4 to 6 hours. This means that it is hard, likely impossible, to maintain aspirin levels continuously within the uricosuric range without risking overdose and other adverse effects. Meanwhile, any time the plasma concentration of aspirin drops, the anti-uricosuric effects can kick in.

Secondly, the analgesic and anti-inflammatory actions of NSAIDs are more useful in combating acute gouty attacks. However, during acute gouty attacks, uricosuric agents are contraindicated. During gout attacks, uric acid is already mobilising out of the joints, and plasma levels are elevated. Forcing more uric acid out through the kidneys with uricosuric agents can increase the risk of kidney stones and kidney damage. Moreover, rapidly reducing plasma concentrations of uric acid creates a concentration gradient from the joints to the plasma causing more uric acid to mobilise from the joints. During mobilisation of the monosodium urate crystals, there is a greater chance of attack on the crystals by the body’s immune system.  This increases the risk of making the gouty attack worse and triggering further gout attacks at other joints.

 

Low-dose aspirin plus glycine for anti-platelet drug therapy

Why do some low-dose aspirin formulations intended for use as anti-platelet medications contain glycine?

Aspirin has a potent anti-platelet action because it is an irreversible inhibitor of cyclooxygenase (COX). COX-1 is required for synthesis of the prothrombotic factor, thromboxane A2 (TXA2), in platelets. Platelets, being fragments of megakaryocytes, do not have a nucleus and therefore cannot synthesise more COX when it is irreversibly inhibited by aspirin. Thus,  to recover from irreversible inhibition of COX-1 in the platelets, your body has to make new platelets. The average lifespan of a platelet is 8 to 9 days, so the anti-platelet effect aspirin is potent and long-lasting. However, in the stomach, inhibition of COX-1 prevents the production of protective prostaglandins and results in increased risk of gastrointestinal disturbance and peptic ulcers.

The combination of aspirin with glycine is reported to improve gastrointestinal tolerance to aspirin for anti-platelet drug therapy (1).  Glycine is also itself reported to have an anti-platelet effect (2).  The evidence to date for the efficacy of glycine both in improving gastrointestinal tolerance of aspirin and in having anti-platelet actions is limited. However, as glycine is a common dietary amino acid, there is little concern over the risk-to-benefit ratio of including glycine in aspirin formulations for use in anti-platelet drug therapy.

References:
(1) Kusche W, Paxinos R, Haselmann J, Schwantes U, Breddin HK. Acetylsalicylic acid tablets with glycine improve long-term tolerability in antiplatelet drug therapy: results of a noninterventional trial. Adv Ther. 2003 Sep-Oct;20(5):237-45.

(2) Schemmer P, Zhong Z, Galli U, Wheeler MD, Xiangli L, Bradford BU, Conzelmann LO, Forman D, Boyer J, Thurman RG. Glycine reduces platelet aggregation. Amino Acids. 2013 Mar;44(3):925-31. doi: 10.1007/s00726-012-1422-8.

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