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When it comes to commonly used painkillers, there are so many different types and categories that it can be quite tricky to get a clear overview. But did you actually realise? All commonly used painkillers work by the same way: Inhibition of Cyclooxygenase - or short COX! This isn’t just true for the well-known non-steroidal anti-inflammatory drugs (NSAIDs), but also for medications like metamizole and paracetamol. So, the term “NSAIDs” is actually outdated and misleading — COX-inhibitors would be a much more accurate way to describe them as a common group of medications! The term “non-steroidal analgesics” also suggests that steroids are analgesics — which is not correct either! Cyclooxygenase inhibitors (COX inhibitors) are medications that reduce inflammation, alleviate pain, and lower fever. They are widely used in conditions such as arthritis, injuries, infections, and other inflammatory diseases. The way these drugs influence COX though is different and therefore is their mode of action.
There are 3 kinds of COX inhibitors: Non-Selective COX inhibitors: (e.g. ibuprofen and naproxen) inhibit both COX 1 and COX2. They are effective but can irritate the gastrointestinal tract. Selective COX-2 inhibitors: (e.g. etoricoxib, celecoxib) primarily inhibit COX-2 and are designed to avoid stomach-related side effects. Central COX inhibitors: Other agents like paracetamol and metamizole act through central COX inhibition and are safer for many patients but lack anti-inflammatory properties.  All COX inhibitors offer pain and fever reduction. However, anti-inflammatory effects are only seen with COX-2 inhibition. Platelet inhibition, important for cardiovascular protection, is achieved through COX-1 inhibition (e.g., aspirin). The selective inhibition of COX-2 alone is sufficient to achieve maximum analgesic and anti-inflammatory effects. Recognising the fact that COX-2 inhibition is sufficient for therapeutic effects, while COX-1 inhibition causes many side effects, led to the development of selective COX-2 inhibitors - so called Coxibs. Although COX-2 selectivity is beneficial, concurrent COX-1 inhibition (e.g., with aspirin) may reduce cardiovascular risk. Selectivity is based on a small structural difference between COX-1 and COX-2 (isoleucine vs. valine at position 523). All Coxibs inhibit COX-2 in the central nervous system as well. Benefits of Coxibs:
Even with all their advantages, COX-2 inhibitors (Coxibs) haven’t completely taken over the NSAID world—and there are some good reasons: Coxibs are a valuable option—especially for patients at high GI risk—but they haven’t replaced non-selective NSAIDs because of: Let's have a closer look at the most common COX-inhibitors used. DiclofenacDiclofenac is a fast-acting, potent non-selective COX inhibitor with slight COX-2 preference (non-selective) and serves as a reference drug for comparing other COX inhibitors. It achieves maximum analgesia through COX-2 inhibition, penetrates inflamed tissue and the CNS well, and has enhanced tissue targeting due to its acidic pKa and plasma protein binding. However, its clinical use is limited by variable absorption, a short half-life (2–4 h), and gastrointestinal and hepatic side effects. High dosing (e.g., 2×75 mg/day) is common but may cause unnecessary adverse effects, including GI erosion and rare severe hepatotoxicity. In general, erosions of the gastric mucosa can be expected after just a few days of use. Protective measures such as proton pump inhibitors or misoprostol cannot prevent direct damage to the mucosal lining. Hepatotoxicity or nephrotoxicity caused by diclofenac is independent of gastric protection. IbuprofenIbuprofen, an arylpropionic acid derivative and preferential COX-1 inhibitor (non-selective), is generally well tolerated, especially at low doses (200–400 mg). At standard daily doses (600–1200 mg), it causes fewer GI side effects than high-dose diclofenac, but at high doses (3×800 mg), its side effect profile (GI and cardiovascular risks) is similar to diclofenac or etoricoxib.
IndometacinIndometacin is a potent COX-1 inhibitor (non-selective) with good penetration into inflamed tissue and the nervous system. It is mainly used for ankylosing spondylitis, acute gout attacks, and prevention of heterotopic ossification. In obstetrics, it is used to close a patent ductus arteriosus in newborns. Its use is limited by frequent GI and central nervous system side effects, such as headache and dizziness. KetoloracKetorolac, a preferential COX-1 inhibitor (non-selective) is often used as eye drops, but in many countries, it is an important intravenous alternative to morphine for treating postoperative pain. It relieves pain up to six hours and is generally well tolerated. There is an association though with a risk of GI-bleeding and renal failure. By the way: It is an isomer of ibuprofen and structurally related to indometacin. NaproxenNaproxen, also a preferential COX-1 inhibitor (non-selective), is widely used in the U.S. but less so in Europe. Due to its long half-life (12–15 hours) and strong COX-1 affinity, it significantly inhibits platelet aggregation, increasing the risk of gastrointestinal bleeding and interactions with anticoagulants. However, this effect also contributes to its lower cardiovascular risk compared to other COX inhibitors. Acetylsalicylic Acid - AspirinAspirin holds a unique position among COX inhibitors. Developed by Felix Hoffmann, the acetylation of salicylic acid improved its tolerability and broadened its effects. At low doses (50–100 mg/day), aspirin irreversibly inhibits COX-1in platelets, preventing aggregation and offering cardioprotection. This effect persists for several days due to the lack of nucleus in platelets. At higher doses (2–3 g/day), aspirin also inhibits COX-2, producing anti-inflammatory and analgesic effects, but significantly increases gastrointestinal side effects due to its acidic nature (pKa 3.0). Notably, aspirin also inhibits NFκB, iNOS, and COX-2 expression—effects that go beyond enzymatic COX inhibition. Pharmacokinetically, the irreversible COX inhibition means aspirin’s duration of action is not tied to plasma levels. The half-life of salicylic acid increases with dose due to enzyme saturation. Indications:
325 mg tablets, common in the U.S., are considered unnecessarily high for cardiovascular prevention. ParacetamolParacetamol (acetaminophen) is widely used as a first-choice analgesic and antipyretic for mild to moderate pain, especially in children, pregnant women, and the elderly, due to its low side-effect profile. Did you know: The IV form (Perfalgan®)offers the most effective analgesia! Despite recurring concerns about safety, especially in high doses or misuse, paracetamol remains one of the safest options when used correctly--no COX inhibitor matches its safety at equal analgesic doses. Mechanism of Action:
Paracetamol has NO Anti-inflammatory Effect! Though it inhibits COX-2, paracetamol has no anti-inflammatory effect. This is because it can’t reduce the high peroxide levels in inflammatory cells needed to block PGH2 synthesis effectively. MetamizoleMetamizole (also known as dipyrone) is a potent analgesic, antipyretic, and spasmolytic drug used for severe pain, including tumor pain, high fever, and biliary or urinary colic. It's a prodrug and rapidly converted to 4-MAA, a reversible, non-selective COX-1/COX-2 inhibitor with central nervous activity. Its COX inhibition is comparable to diclofenac or ibuprofen and likely explains its strong analgesic effect. However, it does not reduce inflammation, and unlike other COX inhibitors. Metamizole:
This lack of typical COX-inhibitor side effects may be due to biochemical antagonism of anti-inflammatory pathways. At high doses, metamizole opens potassium channels and reduces calcium influx in smooth muscles, relieving colic pain but also contributing to blood pressure drops. Despite its clinical usefulness, long-term safety data is limited, especially regarding rare but serious side effects like agranulocytosis. Conclusion
Want to get more insight into this topic, read this excellent article on COX-inhibitors (Original in German): 
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