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Mechanism of action of aspirin

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Tridimensional model of the chemical structure of aspirin.

Aspirin causes several different effects in the body, mainly the reduction of inflammation, analgesia (relief of pain), the prevention of clotting, and the reduction of fever. Much of this is believed to be due to decreased production of prostaglandins and TXA2. Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme.[1] This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors; aspirin creates an allosteric change in the structure of the COX enzyme.[2] However, other effects of aspirin, such as uncoupling oxidative phosphorylation in mitochondria,[3] and the modulation of signaling through NF-κB, are also being investigated. Some of its effects are like those of salicylic acid, which is not an acetylating agent.

Effects on cyclooxygenase

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See also: Cyclooxygenase
Structure of COX-2 inactivated by Aspirin. In the active site of each of the two enzymes, Serine 516 has been acetylated. Also visible is the salicylic acid which has transferred the acetyl group, and the heme cofactor.

There are at least two different cyclooxygenase isozymes: COX-1 (PTGS1) and COX-2 (PTGS2). Aspirin is non-selective and irreversibly inhibits both forms[4] (but is weakly more selective for COX-1[5]). It does so by acetylating the hydroxyl of a serine residue at the 530 amino acid position.[6] Normally COX produces prostaglandins, most of which are pro-inflammatory, and thromboxanes, which promote clotting. Aspirin-modified COX-2 produces 15-epi-lipoxins, which act to resolve inflammatory responses similar to other lipoxins.[7]

Newer NSAID drugs called COX-2 selective inhibitors have been developed that inhibit only COX-2, with the hope for reduction of gastrointestinal side-effects.[8] However, several COX-2 selective inhibitors have subsequently been withdrawn after evidence emerged that COX-2 inhibitors increase the risk of heart attack.[9] The underlying mechanism for the deleterious effect proposes that endothelial cells lining the microvasculature in the body express COX-2, whose selective inhibition results in levels of prostaglandin I2 (PGI2, prostacyclin) down-regulated relative to thromboxane (since COX-1 in platelets is unaffected).[citation needed] Thus, the protective anti-coagulative effect of PGI2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems.[citation needed] As platelets have only mitochondria DNA (mtDNA), they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference between aspirin and the reversible inhibitors.[10]

Effects on prostaglandins and thromboxanes

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Prostaglandins are local chemical messengers that exert multiple effects including but not limited to the transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. They are produced in response to the stimulation of phospholipids within the plasma membrane of cells resulting in the release of arachidonic acid (prostaglandin precursor).[11] Thromboxanes are responsible for the aggregation of platelets that form blood clots.[12]

Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation.[13] This effect is mediated by the irreversible blockage of COX-1 in platelets, since mature platelets don't express COX-2.[14]

This antiplatelet property makes aspirin useful for reducing the incidence of heart attacks;[13] heart attacks are primarily caused by blood clots, and their reduction with the introduction of small amounts of aspirin has been seen to be an effective medical intervention.[citation needed] A dose of 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A2 release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.[15]

A side-effect of aspirin mechanism is that the ability of the blood in general to clot is reduced, and excessive bleeding may result from the use of aspirin.[16]

Other methods of action

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Aspirin has been shown to have three additional modes of action. It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from the intermembrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons.[17] In short, aspirin buffers and transports the protons, acting as a competitor to ATP synthase. When high doses of aspirin are given, aspirin may actually cause hyperthermia due to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses.

Additionally, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduces leukocyte adhesion, which is an important step in immune response to infection. There is currently insufficient evidence to show that aspirin helps to fight infection.[18]

More recent data also suggests that salicylic acid and its derivatives modulate signaling through NF-κB.[19] NF-κB is a transcription factor complex that plays a central role in many biological processes, including inflammation.

Reye's syndrome

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See also: Reye's syndrome

Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing hypoglycemia.[20] The exact cause is unknown, and while it has been associated with aspirin consumption by children with viral illness, it also occurs in the absence of aspirin use.

The disease causes fatty liver with minimal inflammation and severe encephalopathy (with swelling of the brain). The liver may become slightly enlarged and firm, and there is a change in the appearance of the kidneys. Jaundice is not usually present.[21]

Early diagnosis is vital; while most children recover with supportive therapy, severe brain injury or death are potential complications.

See also

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References

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  1. ^ Tóth L, Muszbek L, Komáromi I (March 2013). "Mechanism of the irreversible inhibition of human cyclooxygenase-1 by aspirin as predicted by QM/MM calculations". Journal of Molecular Graphics & Modelling. 40: 99–109. doi:10.1016/j.jmgm.2012.12.013. PMID 23384979.
  2. ^ Giménez-Bastida JA, Boeglin WE, Boutaud O, Malkowski MG, Schneider C (January 2019). "Residual cyclooxygenase activity of aspirin-acetylated COX-2 forms 15 R-prostaglandins that inhibit platelet aggregation". FASEB Journal. 33 (1): 1033–1041. doi:10.1096/fj.201801018R. PMC 6355089. PMID 30096040.
  3. ^ Jörgensen TG, Weis-Fogh US, Nielsen HH, Olesen HP (November 1976). "Salicylate- and aspirin-induced uncoupling of oxidative phosphorylation in mitochondria isolated from the mucosal membrane of the stomach". Scandinavian Journal of Clinical and Laboratory Investigation. 36 (7): 649–654. doi:10.1080/00365517609054490. PMID 1019575.
  4. ^ Vane JR, Botting RM (June 2003). "The mechanism of action of aspirin". Thrombosis Research. 110 (5–6): 255–258. doi:10.1016/S0049-3848(03)00379-7. PMID 14592543.
  5. ^ Kerola M, Vuolteenaho K, Kosonen O, Kankaanranta H, Sarna S, Moilanen E (January 2009). "Effects of nimesulide, acetylsalicylic acid, ibuprofen and nabumetone on cyclooxygenase-1- and cyclooxygenase-2-mediated prostanoid production in healthy volunteers ex vivo". Basic & Clinical Pharmacology & Toxicology. 104 (1): 17–21. doi:10.1111/j.1742-7843.2008.00332.x. PMID 19152549.
  6. ^ Vane JR, Botting RM (June 2003). "The mechanism of action of aspirin". Thrombosis Research. In Honour of Sir John Vane, F.R.S., Nobel laureate, the Discoverer of the Machanism of Action of Aspirin, Krakow, 31 May-3 June 2003. 110 (5–6): 255–258. doi:10.1016/S0049-3848(03)00379-7. PMID 14592543.
  7. ^ Chandrasekharan JA, Sharma-Walia N (September 2015). "Lipoxins: nature's way to resolve inflammation". Journal of Inflammation Research. 8: 181–192. doi:10.2147/JIR.S90380. PMC 4598198. PMID 26457057.
  8. ^ Warner TD, Mitchell JA (October 2002). "Cyclooxygenase-3 (COX-3): filling in the gaps toward a COX continuum?". Proceedings of the National Academy of Sciences of the United States of America. 99 (21): 13371–13373. Bibcode:2002PNAS...9913371W. doi:10.1073/pnas.222543099. PMC 129677. PMID 12374850.
  9. ^ Varga Z, Sabzwari SR, Vargova V (April 2017). "Cardiovascular Risk of Nonsteroidal Anti-Inflammatory Drugs: An Under-Recognized Public Health Issue". Cureus. 9 (4): e1144. doi:10.7759/cureus.1144. PMC 5422108. PMID 28491485.
  10. ^ Peng N, Guo L, Wei Z, Wang X, Zhao L, Kang L, et al. (November 2023). "Platelet mitochondrial DNA methylation: A novel biomarker for myocardial infarction - A preliminary study". International Journal of Cardiology. 398: 131606. doi:10.1016/j.ijcard.2023.131606. PMID 37996014. S2CID 265395351.
  11. ^ Sherwood L (2013). Human Physiology: from Cells to Systems. Belmont, CA: Brooks/Cole, Cengage Learning. p. 758.
  12. ^ Szczuko M, Kozioł I, Kotlęga D, Brodowski J, Drozd A (October 2021). "The Role of Thromboxane in the Course and Treatment of Ischemic Stroke: Review". International Journal of Molecular Sciences. 22 (21): 11644. doi:10.3390/ijms222111644. PMC 8584264. PMID 34769074.
  13. ^ a b "Aspirin in Heart Attack and Stroke Prevention". American Heart Association. Archived from the original on 1 November 2004. The American Heart Association recommends aspirin use for patients who've had a myocardial infarction (heart attack), unstable angina, ischemic stroke (caused by blood clot) or transient ischemic attacks (TIAs or "little strokes"), if not contraindicated. This recommendation is based on sound evidence from clinical trials showing that aspirin helps prevent the recurrence of such events as heart attack, hospitalization for recurrent angina, second strokes, etc. (secondary prevention). Studies show aspirin also helps prevent these events from occurring in people at high risk (primary prevention).
  14. ^ Smith, William L.; Langenbach, Robert (2001-06-15). "Why there are two cyclooxygenase isozymes". The Journal of Clinical Investigation. 107 (12): 1491–1495. doi:10.1172/JCI13271. ISSN 0021-9738. PMC 200199. PMID 11413152.
  15. ^ Tohgi H, Konno S, Tamura K, Kimura B, Kawano K (October 1992). "Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin". Stroke. 23 (10): 1400–1403. doi:10.1161/01.STR.23.10.1400. PMID 1412574. S2CID 14177039.
  16. ^ Amrein PC, Ellman L, Harris WH (May 1981). "Aspirin-induced prolongation of bleeding time and perioperative blood loss". JAMA. 245 (18): 1825–1828. doi:10.1001/jama.1981.03310430017013. PMID 7014935.
  17. ^ Somasundaram S, Sigthorsson G, Simpson RJ, Watts J, Jacob M, Tavares IA, et al. (May 2000). "Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat". Alimentary Pharmacology & Therapeutics. 14 (5): 639–650. doi:10.1046/j.1365-2036.2000.00723.x. PMID 10792129.
  18. ^ Paul-Clark MJ, Van Cao T, Moradi-Bidhendi N, Cooper D, Gilroy DW (July 2004). "15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation". The Journal of Experimental Medicine. 200 (1): 69–78. doi:10.1084/jem.20040566. PMC 2213311. PMID 15238606.
  19. ^ McCarty MF, Block KI (September 2006). "Preadministration of high-dose salicylates, suppressors of NF-kappaB activation, may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy". Integrative Cancer Therapies. 5 (3): 252–268. doi:10.1177/1534735406291499. PMID 16880431.
  20. ^ "Reye syndrome" at Dorland's Medical Dictionary
  21. ^ Suchy FJ, Sokol RJ, Balistreri WF (2007). Liver Disease in Children. Cambridge: Cambridge University Press. ISBN 978-0-521-85657-7.
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