Ketoprofen Ketoprofen, unlike many NSAIDs, inhibits the synthesis of leukotrienes and leukocyte migration into inflamed joints in addition to inhibiting the biosynthesis of prostaglandins. Ketoprofen stabilizes the lysosomal membrane during inflammation, resulting in decreased tissue destruction. Although it is less potent than indomethacin, its gastrotoxicity is about the same. Ketoprofen may cause photosensitivity. The analgesic effect of 30 mg of ketorolac is similar to 10 mg of morphine.

Only moderate anti-inflammatory activity. Anti-inflammatory activity is achieved only at doses higher than those needed for analgesia. Often used in multimodal analgesia to provide an opioid-sparing effect.

Ketorolac has the highest incidence of side effects. The risk of adverse effects is higher when ketorolac is used in higher doses, in elderly patients, and for more than 5 days.

Lornoxicam Lornoxicam is unique among the enolic acid derivatives in that it has a rapid onset of action and a relatively short half-life 3 to 5 hours. Meloxicam Meloxicam was initially introduced as a selective COX-2 inhibitor. However, it is less selective for COX-2 than is celecoxib. Meloxicam causes fewer GI complications than piroxicam. Metamizol Metamizol is a potent and promptly acting analgesic and antipyretic.

Its anti-inflammatory activity is poor. Metamizol was banned in the USA and some European countries due to several reported cases of agranulocytosis. But iIt has been extensively used in India and other European countries. However, adverse effects data collected over 4 decades shows that risk of toxicity with metamizol is lower than with aspirin. Nabumetone Nabumetone represents a new class of non-acidic prodrugs.

Based on available data, nabumetone does not appear to be associated with increased cardiovascular risk 5. Nabumetone may cause photosensitivity. Naproxen has a lowest risk of provoking heart attacks and does not appear to significantly increase CV risks. Naproxen is considered to be the preferred nonselective NSAID for patients with high cardiovascular risk Naproxen provides effective relief in acute traumatic injury and for acute pain associated with migraine, tension headache, postoperative pain, postpartum pain, pain consequent to various gynecologic procedures, and the pain of dysmenorrhea.

May cause increase in blood pressure Over-the-counter formulations are available. Nimesulide Nimesulide is currently approved in many countries worldwide, however several national health authorities have withdrawn nimesulide from the market and others have never approved this drug. Nimesulide exerts COX-2 selectivity similar to celecoxib. Nimesulide works also through a different non-COX pathways that contribute to its potent analgesic and antiinflammatory activity.

Nimesulide has a short half-life and very rapid onset of analgesic action. Its use is restricted to several days due to the risk of hepatotoxicity Oxaprozin Oxaprozin has a rapid onset of action and a prolonged duration of action half-life ranges from 26 to 92 hours. It is mainly used as an anti-inflammatory agent. Oxaprozin also has uricosuric properties and is used in the treatment of gout.

May cause rash and mild photosensitivity. Piroxicam Piroxicam is a long-acting potent NSAID with anti-inflammatory potency similar to indomethacin and good analgesic and antipyretic actions. The main advantage of piroxicam is its hour plasma half-life, which permits a single daily dosing.

Piroxicam is indicated for long-term use in rheumatoid arthritis and osteoarthritis. Its gastrotoxicity is relatively high. Sulindac Sulindac, an analog of indomethacin, is unique among the NSAIDs in not inhibiting prostaglandin synthesis in the kidneys 6.

This process yields aspirin and acetic acid , which is considered a byproduct of this reaction. Small amounts of sulfuric acid and occasionally phosphoric acid are almost always used as a catalyst. This method is commonly employed in undergraduate teaching labs. Many drugs are receiving regulatory approval for only a single crystal form or polymorph. For a long time, only one crystal structure for aspirin was known.

That aspirin might have a second crystalline form was suspected since the s. The elusive second polymorph was first discovered by Vishweshwar and coworkers in , [] and fine structural details were given by Bond et al. In the unambiguous form I, two salicylic molecules form centrosymmetric dimers through the acetyl groups with the acidic methyl proton to carbonyl hydrogen bonds , and in the newly claimed form II, each salicylic molecule forms the same hydrogen bonds with two neighboring molecules instead of one.

With respect to the hydrogen bonds formed by the carboxylic acid groups, both polymorphs form identical dimer structures. Mechanism of action of aspirin Discovery of the mechanism[ edit ] In , British pharmacologist John Robert Vane , then employed by the Royal College of Surgeons in London, showed aspirin suppressed the production of prostaglandins and thromboxanes.

Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the PTGS enzyme Suicide inhibition. This makes aspirin different from other NSAIDs such as diclofenac and ibuprofen , which are reversible inhibitors. Low-dose aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation during the lifetime of the affected platelet 8—9 days. This antithrombotic property makes aspirin useful for reducing the incidence of heart attacks in people who have had a heart attack, unstable angina, ischemic stroke or transient ischemic attack.

Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are caused primarily by blood clots, and low doses of aspirin are seen as an effective medical intervention for acute myocardial infarction.

COX-2 normally produces prostanoids, most of which are proinflammatory. Aspirin-modified PTGS2 produces lipoxins, most of which are anti-inflammatory. Thus, the protective anticoagulative effect of PGI2 is removed, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new PTGS once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors.

Furthermore, aspirin, while inhibiting the ability of COX-2 to form pro-inflammatory products such as the prostaglandins , converts this enzyme's activity from a prostaglandin-forming cyclooxygenase to a lipoxygenase -like enzyme: These mediators possess potent anti-inflammatory activity.

It is proposed that this aspirin-triggered transition of COX-2 from cyclooxygenase to lipoxygenase activity and the consequential formation of specialized proresolving mediators contributes to the anti-inflammatory effects of aspirin.

It uncouples oxidative phosphorylation in cartilaginous and hepatic mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons. When high doses are given, it may actually cause fever, owing to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses.

In addition, 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 reduced leukocyte adhesion is an important step in the immune response to infection; however, evidence is insufficient to show aspirin helps to fight infection.

Aspirin is readily broken down in the body to salicylic acid, which itself has anti-inflammatory, antipyretic, and analgesic effects. In , salicylic acid was found to activate AMP-activated protein kinase , which has been suggested as a possible explanation for some of the effects of both salicylic acid and aspirin. Acetylation of cellular proteins is a well-established phenomenon in the regulation of protein function at the post-translational level.

Aspirin is able to acetylate several other targets in addition to COX isoenzymes. Pharmacokinetics[ edit ] Acetylsalicylic acid is a weak acid , and very little of it is ionized in the stomach after oral administration.

Acetylsalicylic acid is quickly absorbed through the cell membrane in the acidic conditions of the stomach. The increased pH and larger surface area of the small intestine causes aspirin to be absorbed more slowly there, as more of it is ionised.

Owing to the formation of concretions, aspirin is absorbed much more slowly during overdose, and plasma concentrations can continue to rise for up to 24 hours after ingestion. Saturation of binding sites leads to more free salicylate and increased toxicity. The volume of distribution is 0. Acidosis increases the volume of distribution because of enhancement of tissue penetration of salicylates. Conjugation with glycine forms salicyluric acid , and with glucuronic acid to form two different glucuronide esters.

The conjugate with the acetyl group intact is referred to as the acyl glucuronide; the deacetylated conjugate is the phenolic glucuronide. These metabolic pathways have only a limited capacity. Small amounts of salicylic acid are also hydroxylated to gentisic acid. With large salicylate doses, the kinetics switch from first-order to zero-order, as metabolic pathways become saturated and renal excretion becomes increasingly important.

A to fold increase in renal clearance occurs when urine pH is increased from 5 to 8. The use of urinary alkalinization exploits this particular aspect of salicylate elimination.

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