Category: NSAIDs

Dose-dependence of COX-2 selectivity of coxibs

May 9, 2021 / / 0 Comments

Coxibs are pro-thrombotic, but if given at a high dose, there would be COX-1 inhibition resulting in an antiplatelet effect and hence bleeding would occur. Therefore, would the two effects not cancel each other out, or would the prothrombic effect still be the predominant effect?

The pro-thrombotic effect still dominates since, for coxibs, the COX-2 inhibition is always more than the COX-1 inhibition.

Coxibs are selective inhibitors of COX-2. Selective inhibition of COX-2 results in shunting of the precursor arachidonic acid over to the COX-1 pathway. With COX-2 inhibited and COX-1 functional, there is a relative increase in the ratio of the thromboxane A2 (TXA2) produced via COX-1 to prostaglandin I2 (PGI2) or prostacyclin produced via COX-2, and also in some cell types via COX-1. As TXA2 promotes platelet aggregation, while PGI2 inhibits platelet aggregation, the increased ratio of TXA2 over PGI2 favours platelet aggregation, so there is an increased risk of thrombosis.

Although coxibs are selective for COX-2, the selectivity is dose-dependent. Therefore, at higher doses, there will be more inhibition of COX-1. However, in the case of the balance between the risk of thrombosis versus the risk of bleeding, there is little impact because, as the dose increases, there will still be more inhibition of COX-2 than COX-1. So the ratio of TXA2 to PGI2 remains in favour of thrombosis.

Importantly, the dose-dependence of the selectivity for COX-2 is significant with regards to the gastrointestinal adverse effects. A major advantage of the coxibs is that they have a lower risk of upper gastrointestinal tract (GIT) adverse effects as they do not inhibit COX-1 in the stomach. However, if the dose is increased, there is greater inhibition of COX-1 and, therefore, less sparing from upper GIT adverse effects.

Choice of NSAID for closure of patent ductus arteriosus?

May 9, 2021 / / 0 Comments

Why is indometacin a drug of choice for closing the ductus arteriosus post-partum? As the ductus arteriosus is kept open by PGE2, may I know why other NSAIDs or paracetamol are not as ideal for this purpose?

The ductus arteriosus allows blood to bypass the lungs in utero but should close after birth. Cyclo-oxygenase-2 (COX-2) mediated production of prostaglandin E2 (PGE2) is important in keeping the ductus arteriosus open in utero. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-2 when administered at analgesic and anti-inflammatory doses. Therefore, the risk of premature closure of the ductus arteriosus is one reason for the contraindication of NSAIDs in the third trimester of pregnancy.

Patent ductus arteriosus (PDA) occurs when the ductus arteriosus fails to close after birth. NSAIDs can help to close the PDA. Older NSAIDs are typically used because there is a longer history of use and so better knowledge of the risks in infants. Either indometacin, also known as indomethacin (USAN), or ibuprofen is usually used. Paracetamol has also been used as it is has been considered safer in young children. It is not as effectively or widely used, but that it works at all shows that paracetamol can in certain situations inhibit COX-2 in vivo outside of the CNS. Newer NSAIDs are typically not preferred as clinical trials rarely include newborn infants, and so their safety in infants is poorly understood.

Paracetamol for osteoarthritis or rheumatoid arthritis?

May 9, 2021 / / 0 Comments

Some guidelines say paracetamol is only suitable for osteoarthritis, not rheumatoid arthritis (RA), as it is a poor anti-inflammatory. However, further reading online indicates that paracetamol is still used for other inflammatory rheumatological disorders like gout and RA. May I seek further clarification on this point?

Paracetamol (acetaminophen) is no longer recommended as a first-line for the pain associated with osteoarthritis (OA) as it has only small, non-clinically significant effects on the pain and there are safety concerns over long-term use for osteoarthritis (e.g., Macahdo et al., 2015; Roberts et al., 2016). Previously, paracetamol alone was used for the pain associated with OA if there was no significant inflammation following the damage to the joints. However, paracetamol is rarely sufficient for the pain associated with gout or RA. As there is always inflammation in gout and RA, a drug that is both analgesic and anti-inflammatory, such as a non-steroidal anti-inflammatory drug (NSAID), is usually preferable. So you will typically find paracetamol in evidence-based medicine guidelines for OA but not for RA or gout.

However, paracetamol will still cause analgesia. Therefore, you will still find it used sometimes as a safer option in cases when the pain is mild or as an addon between doses of ibuprofen (which happens to have a similar dosing interval) to provide additional analgesia. In addition, for patients for whom NSAIDs are contraindicated, you will often find paracetamol used.

References:
Machado GC, Maher CG, Ferreira PH, Pinheiro MB, Lin CW, Day RO, McLachlan AJ, Ferreira ML. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015;350:h1225.
Roberts E, Delgado Nunes V, Buckner S, Latchem S, Constanti M, Miller P, Doherty M, Zhang W, Birrell F, Porcheret M, Dziedzic K, Bernstein I, Wise E, Conaghan PG. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis. 2016;75(3):552.

Why doesn’t the pro-thrombotic effect of coxibs cancel their impairment of wound healing?

May 9, 2021 / / 0 Comments

Coxibs have both pro-thrombotic and impairment of wound healing effects. So why don’t these cancel each other out?

Thrombosis and impairment of wound healing are not contradictory. Instead, wound healing is a complex process that occurs over days to weeks, and even sometimes months or years, involving the recruitment of a cascade of many cell types.

Haemostasis, which is dependent on COX-1 and platelet aggregation, is only a small component of wound healing that occurs over seconds to minutes when there is bleeding. All the rest of the process over subsequent days and weeks depends on cascades initiated by COX-2-dependent mechanisms. When there is tissue damage without bleeding, all the rest of the COX-2-dependent processes still occur without the need for thrombosis. So even if there is enhanced thrombosis, there can still be impaired wound healing.

Bismuth subsalicylate antacid versus antidiarrhoeal?

May 9, 2021 / / 0 Comments

Bismuth compounds would aid peptic ulcer disease and acute diarrhoea. But bismuth subsalicylate inhibits prostaglandin production, and prostaglandins are cytoprotective, so wouldn’t the inhibition of prostaglandins lead to more mucosal damage?

Both subcitrate and subsalicylate bismuth salts (and also subgallate and subnitrate salts) are used.

Theoretically, the subsalicylate is better for diarrhoea because the salicylate additionally acts as an NSAID to reduce inflammation and reduce prostaglandin-mediated activation of chloride channels reducing chloride and hence water in the lumen of the bowel (the opposite effect to lubiprostone).

Meanwhile, theoretically, the subsalicylate is worse for peptic ulcer as it is hydrolyzed to salicylic acid, which will act as a COX inhibitor preventing the production of the prostaglandins. The prostaglandins have protective actions in the stomach, increasing mucosal blood flow, increasing mucus secretion, increasing bicarbonate secretion and, at high concentrations, reducing acid secretion.

In practice, both subsalicylate and non-subsalicylate bismuth compounds are used clinically for both gastric acid-related disease and diarrhoea, and there is no clear evidence of a difference. However, there have not been large, well-designed clinical trials to compare them directly.

NSAIDs increase risk of gastritis and gastric ulcers

May 7, 2021 / / 0 Comments

What is the mechanism for NSAIDs leading to gastric ulcer formation? Can it also cause gastritis?

With high levels of acidity and digestive enzymes, and food movement, the stomach is an aggressive environment for the tissues lining the stomach wall. Prostaglandins mediate endogenous protective mechanisms, including (1) increased mucosal blood flow; (2) increased mucus secretion; (3) increased bicarbonate secretion; and, at high concentrations, (4) reduced acid secretion.

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the cyclo-oxygenase (COX) enzyme. COX is involved in the production of prostanoids, including classical prostaglandins. In the stomach, COX-1 is essential for the production of the protective prostaglandins. Therefore, inhibition of COX by NSAIDs increases the risk of gastritis (the general term for conditions involving inflammation of the lining of the stomach), including gastric ulcers.

Aspirin for prevention of preeclampsia

February 19, 2019 / / 0 Comments

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).

Cyclooxygenase inhibitors for closure of the ductus arteriosus

September 25, 2018 / / 0 Comments

Why is it that older non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or indomethacin, not newer NSAIDs, such as etoricoxib, are used to promote closure of patent ductus arteriosus in preterm infants?

In the fetus, the ductus arteriosus acts as a lung bypass diverting blood from the pulmonary artery into the aorta.  After birth, the ductus arteriosus constricts and is eventually obliterated. In preterm births, the ductus arteriosus may remain patent resulting in insufficient blood flow through the pulmonary circulation and increased risk of mortality.

Prostaglandin E2 (PGE2) is a vasodilator promoting patency of the ductus arteriosus. NSAIDs inhibit the cyclooxygenase (COX) enzyme responsible for producing  PGE2. NSAIDs are therefore contraindicated in the third trimester of pregnancy as they can cause premature closure of the ductus arteriosus in utero. However, in preterm infants, NSAIDs can be valuable in enabling closure of patent ductus arteriosus (PDA).

The NSAIDs used are typically ibuprofen or indomethacin. These are older NSAIDs for which there is a longer history of experience with use in infants. Ibuprofen is generally the preferred agent as it has a lower risk of reducing gastrointestinal and renal blood flow resulting in necrotizing enterocolitis and transient renal insufficiency. The newer coxibs, such as etorixocib, are not used because there is less knowledge of their safety in infants.

Reference:

Philips III, JB (2018) Management of patent ductus ateriosus in preterm infants. Garcia-Prats JA, Fulton DR, Kim MS ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on October 5, 2018).

 

 

Why is aspirin not used in gout?

February 11, 2017 / / 0 Comments

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

February 3, 2017 / / 3 Comments

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.

Recent Posts

Categories

Archives

© 2024 PharmaNUS

Theme by Anders Noren — Up ↑

This website does not offer medical advice. The information on this website is intended to answer frequently asked questions posed by my students. This website is for informational and educational purposes only. Nothing on this website is intended to constitute professional advice for medical diagnosis or treatment. You should not rely on information received via this website for medical, legal, or financial decisions. Always consult with an appropriate professional for advice related to your health. Never disregard professional medical advice or delay in seeking it because of something you have read on this site.
Skip to toolbar