Ibuprofen: The Mechanism of Action Justin Williams English 202C INTRODUCTION The inflammatory response is one that has

many benefits for the body. It causes blood pressure to drop near the traumatized area, allowing for the body to repair the trauma while protecting from infection from foreign agents. However, this necessary response can lead to pain, swelling, and discomfort. In 1763, the first Non-Steroidal AntiInflammatory Drug, sodium salicylate (aspirin), was discovered. NSAIDs have analgesic (pain killing), antipyretic (fever reducing), and anti-inflammatory properties that help to alleviate the discomfort felt from the inflammatory response of the body. While there are many different NSAIDs now being used, Ibuprofen (Advil) has been one of the most widely used over the counter anti-inflammatory drug since Andrew RM Dunlop and colleagues patented it in 1961.3 The purpose of this document is to educate undergraduate level students interested in the biological sciences on the mechanism of action of ibuprofen. Ibuprofen is a non-steroidal anti-inflammatory drug that acts to inhibit the enzyme cyclooxygenase in order to reduce fever, swelling, and pain in the body. Knowledge about basic enzyme kinetics and physiology will be essential for full comprehension of the information presented. A topdown scheme will be used to explain the material, with the major physiological effects of ibuprofen being explained first. This will be followed by an explanation of the biochemical and pharmacological actions of ibuprofen. Finally, the side effects of using Ibuprofen will be addressed.2 THE PHYSIOLOGICAL EFFECTS OF IBUPROFEN2 Ibuprofen is usually administered orally or topically. After absorption into the bloodstream, the active form of the drug can be carried by serum carrier proteins, such as albumin, throughout the body. Ibuprofen then acts to reduce fever, inflammation, and pain for a duration that is dependent upon the dose taken relative to the size of the individual. Once prostaglandin formation has been inhibited, there are a number of events that lead to the effects of the drug. Inhibition of Clot Formation Clotting factors released by platelets and thromboxanes released after cyclooxygenase enzymes modify arachidonic acid are not released under the influence of ibuprofen. These effects inhibit both pathways that lead to thrombosis. Once clotting is inhibited, local blood pressure will not increase and inflammation is inhibited. This reduced pressure allows for easier movement of swollen joints. 2

Figure 1. Swollen Foot Figure 1 shows a swollen ankle and foot. This type of injury can be allayed for a short period of time with NSAIDs like ibuprofen. Image: Ankle swell and internal bleeding by Glen Bowman (Flikr)

Inhibition of the Release of Interleukins Interleukin-1 induces the hypothalamus to increase body temperature in order to fight infection. The synthesis of interleukin-1 is inhibited by ibuprofen in a similar manner to the inhibition of clotting factors in platelets. The physiological result is the prevention of fever and its effects. Reduction of Pain Ibuprofen is effective at reducing pain because of the same inhibition of prostaglandin synthesis that makes it an effective anti-inflammatory. Nerves in the area (which would normally signal to the brain that the body was experiencing pain by the binding of prostaglandins to receptors) are no longer able to receive this signal. The effect on the body is the temporary relief of pain. THE BIOCHEMICAL AND PHRAMACOLOGICAL EFFECTS OF IBUPROFEN All of the physiological effects of ibuprofen are results of the biochemical and pharmacological effects of the drug. When Phospholipase A2 cleaves membrane phospholipids, arachidonic acid is released. Normally in the inflammatory response, the enzyme isoforms cyclooxygenase-1and cyclooxygenase-2 (COX-1 and COX-2) would catalyze the formation of eicosanoids from arachidonic acid. Ibuprofen inhibits both of these enzymes and therefore inhibits the formation of two different types of eicosanoids. COX-1and COX-2 are responsible for the formation of thromboxanes and prostaglandins. When ibuprofen binds to these enzymes, thromboxanes and prostaglandins are unable to be produced. 1

Figure 2. The Inhibitory Effect of Ibuprofen1

SIDE EFFECTS FROM USING IBUPROFEN As with any drug, the misuse of ibuprofen can lead to side effects. Additionally there are other side effects that could result from the use of ibuprofen. Below are some of the side effects along with some physiological explanation of these side effects. Signs of Allergic Reaction to Ibuprofen Individuals who are allergic to ibuprofen have extreme immune responses to the drug. The symptoms are like many other anaphylactic responses to allergens. Some of these symptoms are listed below.4 Muscle Weakness An overactive immune response to Ibuprofen can lead to the body diverting energy stores to the production of antibodies and phagocytic (cell lysing) cells. This leaves less energy for the body to use for movement. Shortness of Breath - Excessive immune responses can lead to swelling of respiratory tissues. This can cause airways to close and a difficulty in the contraction of the diaphragm. This leads to the difficulty of breathing in an anaphylactic response. Non-Allergic Short Term Side Effects Other side effects of using ibuprofen that can occur during the use of the drug are results of the same physiological and biochemical processes that allow for the alleviation of pain and swelling. Some of these are listed below.4 Ringing of the Ears, headache, nervousness, and Dizziness The increase in blood flow can cause an abnormal amount of blood flow in the brain. This can cause neurons to have excess oxygen and nutrients needed to produce neurotransmitters, causing abnormal signaling in the brain and the perception of a ringing sound or dizziness. Heartburn- The lower esophageal sphincter can be weaker with the use of ibuprofen. This can cause stomach acid to reflux back into the esophagus, causing heartburn. Side Effects Associated with Long-Term use of Ibuprofen4 The long term effects of using Ibuprofen can be adverse. These are usually associated with the digestive system and can include stomach ulcers and bleeding stomach. An increased production of stomach acid can cause the stomach to be digested and blood vessels to rupture.

CONCLUSION Ibuprofen is an over the counter NSAID used for a number of reasons. Its antipyretic, anti-inflammatory, and analgesic properties make it extremely helpful in suppressing the inflammatory response. Ibuprofen inhibits cyclooxygenase-1 and cyclooxygenase-2 to shut down the inflammatory response of the body. There are also some side effects to using this drug which include allergic, short term, and long term effects. WORKS CITED 1. Nelson, David, and Michael Cox. Lehninger . 4th. Pp. 358, 799-804. Print. 2. Solomon, Daniel. "UpDoDate." NSAIDs: Mechanism of action. (2012): n. page. Web. 15 Mar. 2012. http://www.uptodate.com/contents/nsaids-mechanism-ofaction 3. "NewsMedical." What is Ibuprofen?. n. page. Web. 15 Mar. 2012. <http://www.news-medical.net/health/What-is-Ibuprofen.asp&xgt;>. 4. . "Ibuprofen." Drugs.com: Drug Information Online. N.p., 03 28 2011. Web. 15 Mar 2012. <http://www.drugs.com/ibuprofen.html>.