NSAIDs (Non-steroidal Anti-inflammatory Drugs) are the world’s most recommended medications to patients dealing with a variety of discomforts and pains. The study described here compares effectiveness, structure-activity relationships, mechanism of action, enzyme activity at 50% concentration (IC50), mechanism of action, and side effects of five prescription drugs and four non-prescription NSAIDs. NSAIDs help to block COX-1 and COX-2 that produce prostaglandins, which reduces pain and body aches.

Abstract

Introduction

1. IbuprofenRashRinging in the earsAcid stomach

2. Naproxen SodiumHeadacheDifficulty breathingStomach pain

3. AspirinHeartburnUpset stomachBleeding ulcers

4. AcetaminophenRashItchingDizziness

5. CelecoxibCoughFeverRash

6. SulindacRashUpset stomachNausea

7. OxaprozinRashUpset stomach

8. EtodolacDiarrheaConstipationStomach pain

9. DiclofenacUpset stomachDiarrheaHeadache

Figure 3. Names, structures, selected side effects for some common over-the-counter (1-4) and prescription (5-9) NSAIDs.2

Figure 2. A graph of NSAIDs inhibiting either COX-1 or COX-2.5

1. Anaizi, Nasr, "Selective COX-2 Inhibitors." The Drug Monitor. N.p., n.d. Web. 22 Oct. 2015.

2. "The PubChem Project." Whats New in PubChem RSS. National Institutes of Health, 6 Sept. 2004. Web. 17 Sept. 2015.

3. Mitchell, J.A., "Inhibitor Expert (Inhibitors, Compound Libraries)." Selleck Chemicals. N.p., 2013. Web. 23 Oct. 2015.

4. "Acetaminophen." New World Encyclopedia. N.p., 17 Aug. 2012. Web. 26 Nov. 2015.

5. Park, Ki, and Anthony A. Bavry. "Risk of Stroke Associated with Nonsteroidal Anti-inflammatory Drugs." Dove Press, 6 Jan. 2014. Web. 26 Nov. 2015.

References

I would like to thank Dr. Harold Rogers for helping me with my research and Brad van Mourik for printing this poster.

Acknowledgments

Non-steroidal Anti-inflammatory Drugs (NSAIDs) are the amongst the most widely used prescribed and over-the-counter drugs. Historically, Vane first discovered that NSAIDs such as aspirin inhibit the production of prostaglandins in 1971. COX (Cyclo-oxygenase) is the main enzyme that catalyzes the biosynthesis of prostaglandins and was purified in 1976; COX-2 was discovered in 1991 by Vane. NSAIDs work by blocking the effects of COX-1 and COX-2 enzymes, where both enzymes produce prostaglandins. Once the enzymes are blocked, inflammation, pain, and fever are reduced. However, only COX-1 produce prostaglandins that activate platelet activity and protects stomach lining.1 As shown in Figure 1, the mechanism of action of NSAIDs inhibits COX-1 that reduces platelet activity and inhibits COX-2 that reduces pain, fever, and inflammation. Figure 2 illustrates a variety of NSAIDs that are either COX-1 or COX-2 selective. Commonly used NSAIDs, both over-the-counter and prescription, are shown in Figure 3, along with names, structures, and side effects.

Figure 1. Mechanism of action of NSAIDs inhibiting COX-1 and COX-2.1 1. Ibuprofen

• Strong inhibitor at COX-1 since it decreases thromboxane which inhibits platelet activity2

• at COX-1: 1.3 µM and at COX-2: 80 µM3

2. Naproxen sodium• Strong inhibitor at COX-2 by inhibiting the conversion of arachidonic acid to prostaglandin involved

with pain, inflammation, and fever2

• at COX-1: 8.7 µM and at COX-2: 5.2 µM3

3. Aspirin• Inhibits at COX-1 by decreasing the synthesis of prostaglandin and platelet activity2

• at COX-1: 3.57 µM and at COX-2: 29.3 µM3

4. Acetaminophen• Does not inhibit either COX-1 or COX-22

• Has no anti-inflammatory properties or effects on platelet activity and does not alter mood2

• May inhibit nitric oxide utilization by neurotransmitter receptors such as N-methyl-D-aspartate2

5. Celecoxib• COX-2 selective only2

• Reduction in apoptosis and in tumor angiogenesis and metastasis2

• at COX-2: 0.04 µM3

6. Sulindac• Stronger inhibitor activity at COX-2 by inhibiting apoptosis pathway that blocks cGMP dependent

phosphodiesterase2

• at COX-1: 120 µM and at COX-2: 63 µM3

Results

Ibuprofen, aspirin and oxaprozin inhibit strongly at COX-1, therefore the drug concentrations that inhibit the enzyme activity at 50% are lower than at COX-2. Naproxen sodium, celecoxib, sulindac, etodolac and diclofenac inhibit strongly at COX-2, therefore the drug concentration that inhibits the enzyme activity at 50% are lower than at COX-1. Research has shown4 that acetaminophen does not inhibit either COX-1 or COX-2 enzymes because acetaminophen does not inhibit either prostaglandins in platelet activity or prostaglandins in body aches respectively. Acetaminophen inhibits prostaglandin in the central nervous system, which raises the body’s pain threshold that regulates the temperature in the brain to reduce fever.

Discussion

7. Oxaprozin• Stronger inhibitor at COX-1, it inhibits prostaglandin synthesis and platelet activity2

• at COX-1: 2.2 µM and at COX-2: 36 µM3

8. Etodolac• Inhibits at COX-2 by inhibiting prostaglandin involved with pain, inflammation and fever2

• at COX-1: 12 µM and at COX-2: 2.2 µM3

9. Diclofenac• Strong inhibitor at COX-2 by inhibiting prostaglandin involved with pain, inflammation and fever2

• at COX-1: 1 µM and at COX-2: 0.1 µM3

The mechanism of NSAIDs can account for which enzyme either COX-1 or COX-2 inhibits stronger and more effective in terms of their values. Each of the nine drugs have similarities and differences of their functional groups that can also account whether a specific functional group inhibits stronger at either COX-1 or COX-2. From the observation, aspirin contains functional groups of carboxylic acid and ester. Out of the three NSAIDs that inhibits stronger at COX-1, aspirin with the ester functional group is relatively more COX-1 selective. Diclofenac contains functional groups of carboxylic acid, aniline, and chloroaniline. Out of the five NSAIDs that inhibits stronger at COX-2, diclofenac with chloroaniline functional group is relatively more COX-2 selective.

Conclusion

Since there are numerous, often harmful side effects that are associated with taking NSAIDs, there is need for much future work to reduce these common side effects, which include but are not limited to headache, upset stomach, bleeding ulcers, diarrhea, and rash. The reduction of these side effects may require indirect changes in the structures of the parent drugs either to remove, modify or add a different functional group. Since all these NSAIDs have at least one aromatic ring or phenyl group (“large structural units”), which are likely required for stability and shape – particularly planarity – the functional groups present on these rings can possibly be the cause of the major side effects and could be the starting points for consideration of modifications. Removing the aromatic ring or phenyl group from each of the NSAIDs might help reduce side effects, but such modifications might also reduce or nullify the desired activity. Modifications that could reduce side effects could encourage patients to take these prescriptions comfortably and reliably. Adding or modifying side-chain different functional groups such as replacing methyl with ethyl, isopropyl or other straight-chain or branched alkane groups (“small structural units”) could also possibly reduce these major side effects. Using current methods in pharmacological and medicinal chemistry to create libraries of candidates bearing a variety of functional groups on each NSAID could produce derivative NSAIDs that might not only reduce these harmful side effects, but may also help patients to save time and money when taking the right medications for their health needs.

Future Work

Structure/Effectiveness of Selected Prescription and Nonprescription NSAIDsAlina Wilkinson and Dr. Harold RogersCalifornia State University, Fullerton