Major And Side Effects Of Nonsteroidal Antiinflammatory Drugs Biology Essay

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The term NSAID is an abbreviation of a class of drugs known as non-steroidal anti-inflammatory drugs. In my opinion, this name was given to this class of drugs to differentiate them from steroids, the other class of anti-inflammatory drugs. In addition to their anti-inflammatory effects, members belonging to the NSAID class possess both analgesic and antipyretic activities. Therefore, NSAIDs are sometimes referred to as aspirin-like drugs (aspirin was the first member of the class to be discovered).

NSAIDS are medications which have a variety of functions upon the human body including anti-inflammatory, analgesic and anti-pyretic effects. NSAIDs, despite their harmful effects towards the gastrointestinal tract and kidneys, are regularly used on a daily basis, although the dangers of these drugs have led to more concerns and limitations over their use. If used carefully, NSAIDs are effective in treating minor illnesses and their side effects do not need to be of much concern. They work by interacting with the cyclooxygenase pathway and limiting the production of prostaglandins. However, prostaglandins are also involved in other processes in the body and it is the cause of this that leads to the dangerous side effects of NSAIDs.

In this essay I will be discussing the major effects of non-steroidal anti-inflammatory drugs, their side effects in addition to their mechanisms of action. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common pain relief medicines readily available over the counter world wide. In fact, according to the American Gastroenterological Association, everyday more than 30 million people take over-the-counter and prescription drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs) for relief from pain, headaches and arthritis (AGA, 2009).

The cyclooxygenase enzyme has two forms. As mentioned by Fletcher et al, there are two enzymatically active isoforms of the cyclooxygenase enzyme, cyclooxygenase-1(COX-1) and cyclooxygenase-2 (COX-2), and went on by saying, both isoforms have similar biological functions and share approximately 60 per cent primary sequence identity (Fletcher et al, 1992). The COX 1 enzyme is present in most cells of the body including the stomach, while the COX 2 enzyme is less abundant in the stomach and is found at the site of inflammatory cells. This explains clearly why the anti-inflammatory effect of the NSAIDS is mainly due to the inhibition of the COX 2 since it is present at the site of inflammatory cells, whereas the side effects caused by the NSAIDS such as ulcer arises as a result of the inhibition of COX 1.

NSAIDS can be divided into two groups depending on their inhibitions of cyclooxygenase (COX) enzyme. If they inhibit both COX enzymes (COX 1 and COX 2), they are called non-selective COX inhibitors. But, if they inhibit only COX 2, then they are known as COX 2 selective inhibitors, for example, Celecoxib (Patient UK, 1997).

When the body is injured or a tissue is damaged, the damaged tissue releases hormones called prostaglandins. These prostaglandins are produced by arachidonic acid to cause inflammation and pain. The inflammatory process causes the release of interleukin-1 resulting in the production of prostaglandins type E (PGE) in the hypothalamus. This initiates an increase in the body temperature. The anti-inflammatory drugs lower the body temperature by bringing it to normal by inhibiting the COX enzyme. As Mozayani, (2004) stated ".......This eventually leads to the body temperature being brought back to normal".

The chemical characteristics of NSAIDs explain the difference in their kinetics, mechanism of action and side effects. NSAIDs work by interfering with the process of making such prostaglandins. In other words, they inhibit the cyclooxygenase pathway by selectively binding onto the arachidonic acid site on the COX enzyme, preventing the migration of arachidonic acid to the active site on the enzyme.

NSAIDS may differ in their mechanisms of action. This is related to the reduction of prostaglandin synthesis by inhibition of COX enzyme through competitive binding to the cyclooxygenase enzyme. NSAIDS within the same chemical group tend to show similar efficacy as long as they are used at equivalent dose (NCBI, 2007).

NSAIDS may also differ in their duration of action. Some of the anti-inflammatory drugs will last for days while others can last for hours. An example of those last for days is aspirin while those last for hours is Ibuprofen. Aspirin is the NSAID of preferred choice to treat blood clots in arteries since it is mode of action will last for days rather than hours like some of the other NSAID (Medicine net, 2007). This is due to the NSAIDS binding to the COX enzyme, as stated by Knodel, (1992) "Aspirin, for example, irreversibly binds to the cyclooxygenase ,whereas Ibuprofen and the other NSAIDs reversibly bind to cyclooxygenase, thereby allowing normal platelet function to return once the drug has been eliminated" (Knodel, 1992).

NSAIDS may also differ in their ability to cause side effects. These side effects may vary from something mild to something more serious such as stomach bleeding (ulcer). Most of the side effects related to NSAIDS treatment are mild. However, there are more serious side effects. The most common of these problems involve the gastrointestinal tract (Knodel, 1992). According to Garnett, it has been estimated that up to 20% of patients on NSAIDs are affected by GI problems (Garnett, 1996).

These side effects are due to their ability to inhibit COX 1. COX 1 is involved in the production of prostaglandins E2 which is responsible for the regulation of gastric acid secretion and the mucus protection in the stomach lining. As McGavock, stated "When PGE2 synthesises is ceased, this causes irritation of the stomach lining and eventually erosion of the mucosal layer" (McGavock, 2005, p.48). In addition to that Wallace (2001) added, the presence of acid in the lumen of the stomach also contributes to the pathogenesis of NSAID-induced ulcers and bleeding by impairing the restitution process and inactivating several growth factors that are important in mucosal defence and repair (Wallace ,2001).

When the NSAIDS inhibit COX 1, they are more likely will cause an ulcer. As Martinez and Badimon clearly stated "......This is why selective COX 2 inhibitors were developed because they only inhibit COX 2 and hence minimising gastrointestinal side-effects"(Martinez and Badimon, 2007).

NSAIDS can be used as anti-pyretics as well as analgesics to treat illnesses such as headaches and backaches. They work by preventing the production of prostaglandins through the inhibiting the COX 2 enzyme to stop nerve stimulation to send pain signal to the brain.

Regarding aspirin is one of the NSAIDS that is commonly prescribed by doctors to treat mild to moderate pain including headache, migraine, fever and other illnesses. There does seem to be strong evidence for its benefit to those with acute myocardial infraction. However, aspirin is not a wonder drug said to treat cardiovascular disease, but is only effective against some types of cardiovascular disease such as strokes and heart attacks due to its anti-clotting properties. As well as having their benefits, they also have side effects such as stomach ulcers, vomiting and nausea. Despite the health risks of aspirin, it is accepted that the greater risk to the patient's life is the myocardial infraction and it is preferred that the patient suffers from the discomfort of stomach ulcers rather than the dangers of cardiovascular disease.

Unlike other NSAIDS, aspirin has the ability to prevent blood clotting from happening by inhibiting thromboxane A2 and prostaglandin formation in the platelets as well as prostaglandin I2 in vascular cells. It prevents platelet aggregation by irreversible acetylation of cyclooxygenase, a key enzyme in the arachidonic acid metabolism(Villa et al,1979). For Patients with cardiovascular diseases such as strokes and heart attacks are prescribed with small dose of aspirin instead of high dose. According to BNF, prescribing the correct dose of NSAIDS for the treatment of blood clot is important because a high dose of NSAIDS can lead to myocardial infraction if used for long term treatment (BNF, 2007, P.524).

Other NSAIDS such as Ibuprofen and paracetamol which can also be prescribed to treat similar illnesses. Both of these drugs differ from aspirin in some or other ways. For instance, according to Mozayani, (2004), Ibuprofen is said to cause less gastrointestinal effects compared to aspirin, whilst paracetamol does not cause any at all. But, as Brunton pointed out aspirin is a better anti-inflammatory drug compared to both of these drugs (Brunton, et al, 2006, P 693). In terms of side effects, paracetamol has fewer side effects in comparison with aspirin and ibuprofen. Aspirin and ibuprofen can result in gastrointestinal side effects and even come depending on the overdose quantity (Netdoctor).

Also heavy use of NSAIDs can lead to high blood pressure and even permanent kidney damage. This is because NSAIDs also reduce the blood flow to the kidneys which makes them work more slowly. Hence fluid builds up in the bloodstream which raises the blood pressure. If this continues, major consequences could follow such as heart failure or, in the case of the kidneys, kidney failure and the patient would require dialysis.

Conclusion

NSAIDS represent an important group of drugs indicated for treatment of inflammation. All members of the NSAIDS act by the same mechanism of action, reduction of prostaglandin synthesis through inhibition of the enzyme cyclooxygenase (COX). They possess antipyretic and analgesic properties; however, only those with strong inhibitory effects on PGs synthesis are useful as anti-inflammatory drugs. The drugs suppress inflammation through inhibiting the production of prostaglandins.

Due to the inhibitory effects on thromboxane (TXA2) biosynthesis, long term use of most of the class members results in decreased blood clotting, which can lead to serious bleeding problems if combined with the development of an ulcer.

It has been shown that aspirin inhibits platelet aggregation. In fact, there is even more evidence to support the positive health effects of aspirin. In the Second International Study of Infarct Survival, more than 1700 men and women within 24 hours of onset of symptoms of suspected myocardial infraction were randomly assigned to 162mg of aspirin or placebo daily for 30 days. After 5 weeks, those who had received aspirin had statistically significant reductions in risk of vascular mortality (23%), non-fatal reinfarction (49%) and non-fatal stroke (46%). The results were such that it leads to The American Heart Association in 1997 claiming that "aspirin has perhaps the best benefit-to-risk ratio of any proven therapy for acute MI" (American Heart Association, 1997). However, there are criticisms of aspirin and its use as a drug to prevent cardiovascular disease. Certainly the health risks of aspirin is a major cause of concern if a patient is to take it regularly

Reference

AGA, 2009. AGA Patient Centre. Available at

http://www.gastro.org/wmspage.cfm?parm1=5815 [Accessed: 29/11/09.

BNF. 2007. (53). British National Formulary. BMJ Publishing Group. P. 524

Brunton, L., John, S., Keith, L., and Parker, L. 2006. The Pharmacological Basis of Therapeutics. Goodman & Gilman's. (11th ed.) p.693

Fletcher, B.S., Kujubu, D.A., Perrin, D. M., and Herschman, H.R. 1992. Structure of the mitogen-inducible TIS10 gene and demonstration that the TIS10 encoded protein is a functional prostaglandin G/H synthase. Journal of Bio Chem. 267, 4338-4344

Knodel, L.C. 1992. NSAID adverse effects and interactions. Who is at risk?" American Pharmacy. NS32(3), 39-47

Marnett, L. J., 2000. Cyclooxygenase Mechanisms. Current Opinion in Chemical Biology. 4(5), 545-552.

McGavock, H. 2005. How drugs work. Basic Pharmacology for Healthcare professionals. (2nd ed) Radcliffe publishing Ltd. P. 48.

Gonzalez, J. M. and Badimon, L. 2007. Mechanisms Underlying the Cardiovascular Effects of COX- inhibition: Benefits and Risks. Bentham Science Publishers. 13 (22), 2215-2227

Mozayani, A. and Rayman, L.P., 2004. Handbook of drug interaction. A clinical and forensic guide. Humana Press. P. 340

NCBI, 2009. Non-steroidal anti-inflammatory agents (NSAIDS) with lesser side effects by selective inhibition of cyclooxygenase -2. Available at

http://www.ncbi.nlm.nih.gov/pubmed/9856140?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 , [ Accessed : 28/11/09].

Patient, UK.1997. Anti-inflammatory Painkillers. Available at:

http://www.patient.co.uk/showdoc/27000440 . [Accessed on 23/11/09]

Villa, S., Iivio, M. A., and Gaetano, G. D.1979. The Inhibitory Effect of Aspirin on Platelet and Vascular Prostaglandins in Rats cannot be completely dissociated.

British Journal of Haematology. 42(3), 425-431. Available online at

http://www3.interscience.wiley.com/journal/120728792/abstract

Wallace, J. 2001. Pathogenesis of NSAID-induced gastroduodenal mucosal injury.

Best Practice and Research Clinical Gastroenterology, 15(5), 691-703. Available online.

www.netdoctor.co.uk/medicines/ [Accessed on 27/11/2009]

ISIS-2 Collaborative Group. 1988. Randomised trial of intravenous streptokinase, oral aspirin, both or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2 Lancet (2)349-360. Available at http://www.incirculation.net/whatswhat/11093_11976.aspx

[Accessed : 30/11/09]

American Heart Association.1997. Inc. Available at

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Vane, J.R. and Botting, R.M., 1971. Inhibition of prostaglandin synthesis as a mechanism of action-like drugs. Thrombosis Research, 110 (2003) 255-258 available online.

HYPERLINK "http://www.webmd.com/reheumatioid-arthritis/guide/how-anti-inflammatory-drugs-work"

www.webmd.com/reheumatioid-arthritis/guide/how-anti-inflammatory-drugs-work

.

But what are they and how do they work?

First of all, to understand how a drug can be analgesic (pain killing) you must first understand what pain is. R. Morgan Griffin, writing for WebMD describes pain as "the result of an electrical signal being sent from your nerves to your brain" and also notes that "the process is not only electrical... the damaged tissue releases chemicals called prostaglandins...cause the tissue to swell. They also amplify the electrical signal coming from the nerves"

. These prostaglandins (which are paracrine secretions) go on to stimulate many body functions; those formed by the COX-1 enzyme are involved in stomach mucus production and kidney water excretion while prostaglandins formed by the isoform COX-2 have an important role in inflammation.

NSAIDs work by interfering with the process of making such prostaglandins, the cyclooxygenase pathway. In normal conditions the first step production of prostaglandins from arachidonic acid is the bis-oxygenation of arachindonate to prostaglandin PGG2. This is followed by reduction to PGH2 in a peroxidase reaction. Both these reactions are catalyzed by cyclooxygenase, (COX) also known as PGH synthase. NSAIDs inhibit this pathway by selectively binding onto the arachidonic acid site on the COX enzyme, preventing the migration of arachidonic acid to the active site on the enzyme. This prevents the formation of prostaglandins and hence less inflammation and less amplification of the electrical signal R.Morgan Griffin was talking about. NSAIDs also work by the inhibition of lipoxygenase, leukotriene synthesis, lysomal enzyme release and neutrophil aggregation. These factors combine lead to the suppression of inflammation and the drug acting as an analgesic agent.

However, as mentioned, not all prostaglandins are used for the stimulation of inflammation. The Cox-1 enzyme helps makes the prostaglandin which is responsible for the protection of the lining of the stomach. NSAIDs block COX-1 enzymes therefore they slow down the production of this prostaglandin. With less mucus in the wall of the stomach, the GI tract can become irritated and damaged by normal gastric acids which can lead to ulcer disease. The drugs also cause damage by the irritant effect of these drugs on the epithelium, reducing the stomach wall blood flow and interfere with the repair of injury.

The presence of acid in the lumen of the stomach also contributes to the pathogenesis of NSAID-induced ulcers and bleeding by impairing the restitution process and inactivating several growth factors that are important in mucosal defence and repair

. These problems cannot be rid of by a change of dosage (i.e. non-oral routes) as although non-oral routes avoid the direct irritation of the stomach, they do not avoid the indigestion and ulcer risks as these are caused by the chemical once it is in the blood stream. It is for this reason that NSAIDs cannot be used in someone with a history of peptic ulcer except in exceptional circumstances with close medical supervision. Also they would rarely be used in somebody with heartburn or indigestion.

Also heavy use of NSAIDs can lead to high blood pressure and even permanent kidney damage. This is because NSAIDs also reduce the blood flow to the kidneys which makes them work more slowly. Hence fluid builds up in the bloodstream which raises the blood pressure. If this continues, major consequences could follow such as heart failure or, in the case of the kidneys, kidney failure and the patient would require dialysis.

Those with asthma are advised to stay away from any NSAID as they seem to cause extreme allergic reactions such as getting more wheezy especially if they have sinus problems. However, the reasons behind this is still unknown.

These side effects are due to the NSAID interfering with the COX-1 enzyme. Drug companies have tried to make their drugs more specific and target only the COX-2 enzyme. This is possible, as although the 2 enzymes are isotopes, the active site of COX-1 is smaller so it accepts a smaller range of structures as substrates. This has lead to the production of COX-2 inhibitors which only bind onto COX-2 enzymes and therefore are designed to avoid the GI problems found in NSAIDs. However problems can occur. In a normal body the levels of COX-1 and COX-2 enzymes are in balance. By blocking COX-2, one is reducing the production of prostacyclin, a chemical which keeps in check the harmful side-products of the reactions that involve COX-1. When COX-2 is solely blocked, the enzymes become unbalanced. Levels of prostacyclin go down, the influence of COX-1 goes unchecked and the risk of heart attacks and strokes goes up. In fact the dangers of these effects were so great that Bextra and Vioxx-2, distinguished COX-2 inhibitors, were taken off the market because of their harmful effects towards those who took them.

Aspirin, originating from willow bark

, is a very popular drug, has often been used as an anti- inflammatory analgesic, much like many other NSAIDs. However in 1971 British Pharmacologist John Robert Vane showed that aspirin suppresses the production of thromboxanes (a member of the family of lipids known as eicosanoids) which is responsible for the aggregation of platelets that form blood clots. For his work, John Vane won the Nobel Prize in 1982. This quality in aspirin perhaps makes it unique in NSAIDs and of special interest to hose in the medical profession in fighting cardiovascular disease.

Cardiovascular disease, which includes myocardial infarction, stroke and peripheral vascular diseases, is the leading cause of death in the United States and many developed countries.

It has been shown that aspirin can reduce risks of occlusive vascular events

. This occurs by inhibiting platelet aggregation. In fact, the evidence was conclusive enough to prompt an update of an earlier American Heart Association statement which is intended to provide clinicians with guidelines for the use of aspirin in treatment and the prevention of cardiovascular disease.

There is even more evidence to support the positive health effects of aspirin. In the Second International Study of Infarct Survival

, more than 1700 men and women within 24 hours of onset of symptoms of suspected MI were randomly assigned to 162mg of aspirin or placebo daily for 30 days. After 5 weeks, those who had received aspirin had statistically significant reductions in risk of vascular mortality (23%), non-fatal reinfarction (49%) and non-fatal stroke (46%). The results were such that it leads to The American Heart Association in 1997 claiming that "aspirin has perhaps the best benefit-to-risk ratio of any proven therapy for acute MI" (American Heart Association, 1997). However, there are criticisms of aspirin and its use as a drug to prevent cardiovascular disease. Certainly the health risks of aspirin is a major cause of concern if a patient is to take it regularly.

It has also been shown that regular long term aspirin therapy has positive health benefits. The 1994 Antiplatelet Trialists' Collaboration overview analyzed results of randomised trials of antiplatelet therapy among about 54000 high risk patients with prior evidence of cardiovascular disease. Among such patients, aspirin therapy reduced the risk of subsequent vascular events by about 25%. This effect was especially evident in middle-aged and older patients.

However, there are criticisms of aspirin and its use as a drug to prevent cardiovascular disease. Certainly the health risks of aspirin is a major cause of concern if a patient is to take it regularly.

The BNF lists the side effects of aspirin: BNF 46, September 2003

"Generally mild and infrequent but high incidence of

gastro-intestinal irritation with slight asymptomatic

blood loss, increased bleeding time, bronchospasm and

skin reactions in hypersensitive patients"

Is it wise to treat those with cardiovascular disease with a drug that can potentially cause quite serious side effects? Such questions concerning the health risks of aspirin relate directly to its dose. The US food and drug administration argued that for aspirin to have an immediate clinical antithrombotic effect, an initial dose of 160 to 162.5mg to be continued daily for at least 30 days as a reasonable prescription. However other sources suggest otherwise, many claiming that lower dosages provide (even as low as 75mg per day

) enough of the active ingredient to be effective. Aspirin has little proof as being useful as a primary prevention drug. In the US Physicians' Health study over 22000 male patients undertook an experiment in which they consumed an alternate-day dose of 325mg of aspirin. Although the results revealed that there was a 44% reduction in risk of the first MI, the findings for stroke as well as the overall cardiovascular mortality were deemed inconclusive due to inadequate number of events. This conclusion was collaborated by a British trial.

References and Sources

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Medinfo,

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J. Wallace, Pathogenesis of NSAID-induced gastroduodenal mucosal injury.

Best Practice & Research Clinical Gastroenterology, Volume 15, Issue 5, October 2001,Pages 691-703, Available online.

HYPERLINK "http://www.sciencedirect.com/science/journal/15216918"

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Sanme as 1

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http://circ.ahajournals.org/cgi/content/full/96/8/2751

ISIS-2 Collaborative Group. 1988. Randomised trial of intravenous streptokinase, oral aspirin, both or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2 Lancet. ( 2)349-360. Available at

HYPERLINK "http://www.incirculation.net/whatswhat/11093_11976.aspx"

http://www.incirculation.net/whatswhat/11093_11976.aspx

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http://circ.ahajournals.org/cgi/content/full/96/8/2751

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Vane, J.R. and Botting, R.M., 1971. Inhibition of prostaglandin synthesis as a mechanism of action-like drugs. Thrombosis Research, 110 (2003) 255-258 available online.

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References and further reading may be available for this article. To view references and further reading you must

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purchase

this article.

Lawrence J Marnett, Cyclooxygenase mechanisms

HYPERLINK "http://www.sciencedirect.com/science/journal/13675931"

Current Opinion in Chemical Biology

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The Inhibitory Effect of Aspirin on Platelet and Vascular Prostaglandins in Rats cannot be completely dissociated. Available online:

HYPERLINK "http://www3.interscience.wiley.com/journal/120728792/abstract"

http://www3.interscience.wiley.com/journal/120728792/abstract

NSAIDs are one of the most frequently prescribed classes of drugs. These medications are used in conditions, such as rheumatoid arthritis, relieving pain associated with dysmenorrhea, dental procedures, and musculoskeletal disorders.1

Most of the side effects associated with NSAID treatment are mild. However, there are more serious adverse effects. The most common of these problems involve the gastrointestinal tract.1 Knodel,1992). According to Garnett, it has been estimated that up to 20% of patients on NSAIDs are affected by GI problems.1,5 (( Garnett,1996)

The damage to the GI tract can occur through direct mucosal injury.1 Aspirin, for example, causes minor mucosal injury and can be locally irritating. The second method of gastric destruction involves the inhibition of gastric prostaglandin synthesis (through cyclooxygenase-1 [COX-1] and cyclooxygenase-2 [COX-2]) and is more serious. These prostaglandins are important for the production of gastric bicarbonate and mucous, and in the maintenance of sub-mucosal blood flow.1 Inhibiting these prostaglandins, specifically COX-1, significantly increases the likelihood of mucosal injury.1,2 Knodel,1992)

DRUG REACTIONS

One of the dangers associated with the development of NSAID-induced gastric ulcers is that most patients remain asymptomatic until complications arise. Although perforation can occur within a few days following initiation of therapy, most complications occur during chronic NSAID use.1 There appears to be a dose-response relationship relative to the extent of gastric injury. Taking NSAIDs with food or at other times does not appear to affect the overall risk of ulceration; however, food may help decrease the direct mucosal irritation. Prophylactic treatment with H2-receptor antagonists,

antacids, and sucralfate has not been shown to be effective in reducing the frequency or severity of these problems.1

NSAIDs exhibit varying degrees of anti-platelet activity by inhibiting platelet cyclooxygenase.2 The resulting thrombocytopenia may contribute to the bleeding associated with GI mucosal damage. There are several parameters which determine the amount of time required for normal platelet function to return. One such factor is the extent to which a drug binds to cyclooxygenase. Aspirin, for example, irreversibly binds to the enzyme, thus inhibiting functioning for the entire life of the thrombocyte.

Platelet activity is then dependent upon the production of new cells, which takes seven to twelve days.1,5 Ibuprofen and the other NSAIDs reversibly bind to cyclooxygenase, thereby allowing normal platelet function to return once the drug has been eliminated.1 For these products, the half-life of the drug ultimately determines how long it will take for normal platelet function to return.5

Although NSAIDs rarely causes adverse effects on the kidneys, there are certain patients that are at an increased risk of developing adverse renal effects. These include patients with congestive heart failure, cirrhosis, hypovolemia, or a pre-existing renal condition.1 Patients who have a history of kidney problems, it is important to monitor their urine output.

There are two distinct processes by which the kidneys are adversely affected.1,2 The first mechanism is an indirect effect on renal perfusion. Prostaglandins enhance the vasodilation of renal vasculature. NSAIDs inhibit prostaglandin production leading to a decrease in renal perfusion which can cause ischemic injury. For those patients at risk, acute renal failure can occur soon after NSAID treatment is begun. It is the reduction in renal perfusion, not the decrease in basal prostaglandin production, which is responsible for the injury.1

The second mechanism of adverse effects is an idiosyncratic reaction that causes an interstitial nephritis. It can occur within days after initiation of therapy or after several months, and appears to be immunologically mediated. Renal function generally recovers after discontinuation of therapy.1

Although NSAIDs are effective in treating many conditions, they have some serious side effects associated with their usage. The most serious of these adverse effects is the possibility of GI damage. NSAID users are at nearly three times greater risk for developing gastric ulcerations, bleeding, and death from these complications that are non-users.5 According to the Food and Drug Administration, these complications are estimated to cause between 10,000 and 20,000 deaths and approximately 76,000 hospitalizations annually, thus making the consequences of NSAID therapy a major public health hazard.1,6 WR Garnett

References

1.LC Knodel. "NSAID adverse effects and interactions. Who is at risk?" American Pharmacy. 1992; NS32:39-47.

2. PA Insel. "Analgesic-antipyretic and anti-inflammatory agents; drugs

employed in the treatment of rheumatoid arthritis and gout." Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th Ed. A Goodman Gilman, TW Rall, AS Nies, P Taylor (eds.). New York: Pergamon Press; 1990: 638-81.

3. Drug Facts and Comparisons. Updated Monthly. St. Louis: Facts and

Comparisons; Pp. 251-252f.02.

4. Clinical Pharmacology (Drug Monograph Service). v. 1.5, Gold Standard Multimedia Inc. (http://www.geohealthweb.com/GHW/private/clinphrm/monographs.html)

5. WR Garnett. "Effects of OTC analgesics: Implications for product selection." Journal of the American Pharmaceutical Association. 1996; NS35:565-570.

6. KE Cooke. "Disease management: Prevention of NSAID-induced gastropathy." Medscape® Continuing Medical Education. May 25, 1996.

(http://www.medscape.com)

American Journal of Pharmaceutical Education 2003; 67 (2) Article 63.

TEACHERS TOPICS

NSAIDs: Chemistry and Pharmacological Actions

Ahmed S. Mehanna, PhD

School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences

Keywords: nonsteroidal anti-inflammatory drugs, analgesics, aspirin-like drugs

INTRODUCTION

The term NSAID is an abbreviation of a class of drugs known as non-steroidal anti-inflammatory drugs. In my opinion, this name was given to this class of drugs to differentiate them from steroids, the other class of anti-inflammatory drugs. In addition to their anti-inflammatory effects, agents belonging to the NSAID class possess both analgesic and antipyretic activities. Hence, NSAIDs are sometimes referred to as aspirin-like drugs (aspirin was the first member of the class to be discovered). The chemical features of NSAIDs explain different aspects of their kinetics, mechanism of action and side effects.

NSAID is an important class of drugs used to relief pain and inflammation in cases of rheumatoid arthritis and other inflammatory diseases. Recently, some NSAIDs have come out as part of a new class of cancer chemotherapeutic and chemo- preventive agents.

1. Disease State of Inflammation and Pros-taglandins Biosynthesis

In a simplified term the inflammation process can be considered as an event of the immune response1 through which tissue damage occurs. The tissue damage is accompanied by the release of many biochemical mediators such as prostaglandins (PGs).

Prostaglandins increase tissue sensitivity to pain and raise the body temperature.

Prostaglandins are a group of local hormones that are endogenously synthesized from arachidonic acid (Figure 1, structure 1). When tissues expose to anything causes inflammation, cell membranes release arachidonic acid by partial hydrolysis of lipids by the membrane-bound enzyme phospholipase.2 Arachidonic acid is subjected to one of the biochemical transformation routes which involves an enzyme called cyclooxygenase (or COX) to produce prostaglandins. The cyclooxygenase enzyme also converts arachidonic acid into another cyclization product called thromboxane (TXA).The biological effects of various prostaglandins and thromboxanes indicate that both PGE and PGF are responsible for increasing tissue sensitivity to pain. The major effect of PGI2 (also called prostacycline) is inhibition of the platelet aggregation process. Due to the important role of prostaglandins in the process of inflammation, inhibiting prostaglandin biosynthesis is the main thing to fighting inflammation. NSAIDS are inhibitors of Prostaglandin biosynthesis.

2. Chemistry and Structure Activity Relation-ships of NSAID

The mechanism of action of NSAIDs involves decreasing the production of prostaglandin by inhibition of COX enzyme through competitive binding to the cyclooxygenase enzyme (COX). For a drug to be an effective competitive inhibitor for arachidonic acid binding to COX, the drug must posses chemical properties that mimic the substrate chemistry. This is clearly apparent in the chemical structures of all NSAIDs such as Ibuprofen3 (structure 6), flubiprofen4 (structure7), ketoprofen5 (structure8), naproxen6 (structure9), indomethacin7 (structure10), diclofenac5 (structure11), and piroxicam5,6 (structure12). The acidic functionality can be a propionic acid carboxylic group (see Figure 2, structures 6, 7, and 8), or an acetic acid carboxylic group (see Figure 2, structures 10 and11), or as an enolic group (acidic proton of 1,3 diketo group; see structure 12). NSAIDs with a polar group in the lipophilic tail such as sulindac8(structure 13) are not effective COX inhibitors before being metabolized into a more lipophilic substance (structure 14) as further explained under the metabolism section of NSAIDs kinetics. In a similar manner, lipophilic drugs lacking the acidic functionality, such as nabumetone9 (structure 15), are metabolized into products with acidic functional groups (structure 16) before becoming active. Therefore, both sulindac and nabumetone are classified as prod-rugs. It is worth noting the correlations between drug generic names and their chemical structures, eg, all propionic acid NSAIDs include the letters "pro" in the name, while acetic acid derivatives include the letters "ac." The names of both nabumetone and naproxen indicate that both are naphthalene derivatives.

3. Kinetics of NSAID

Since all NSAIDs are highly lipophilic substances, members of the class share similar, if not identical, absorption properties. Drug absorption after oral administration is generally rapid and complete. Most NSAIDs are given as oral tablets or capsules; others are given by injection to avoid gastric irritation.

Knowledge of the mechanism of action of NSAIDs, as competitive inhibitors for arachidonic acid binding to COX, provides a good tool to predict whether NSAID metabolites are active or not. Generally, phase-I metabolism of NSAIDs produces more polar products.

4. NSAID Mechanism of Action as Antipyretic, Analgesic, and Anti-Inflammatory Agents

As pointed out earlier, NSAIDs act as anti-inflammatory agents by inhibiting the biosynthesis of the prostaglandins that are classified as inflammation-inducing substances. For a given drug to act as an NSAID, the drug's chemistry must have lipophilic properties and the presence of an acidic functional group. Drugs having either weak lipophilic or weak acidic properties are not expected to be good anti-inflammatory agents. Acetaminophen (structure 17), shows weak properties regarding both lipophilicty and acidity; therefore, it is void of any anti-inflammatory actions. On the other hand, acetylsalicylic acid (structure 18) has poor lipophilic properties but a strong acidic functional group produces anti-inflammatory effects only at much higher doses (10 g) than its analgesic dose of only 1g. Drugs with both strong lipophilic characteristics and strong acidic properties such as members of the acetic and propionic acid series show significant ant-inflammatory actions at much smaller doses (30 mg -100 mg).

In general, NSAIDs show a similar pattern of side effects on the gastrointestinal tract such as nausea, vomiting, and diarrhea. However, the most serious side effect caused by the long term use of NSAIDs is the gastric ulceration. The NSAIDs can irritate the gastric mucosa, through their inhibitory effects on prostaglandin biosynthesis. By inhibiting prostaglandin synthesis, mucin secretion will be indirectly reduced and an increased risk of ulceration happens.

The enzyme COX has 2 sub-types: COX-1 and COX-2. The former exists throughout the biological system including in the stomach, while the second (COX-2) is much less abundant in the stomach. This discovery prompted investigators and researchers to develop selective COX-2 inhibitors to minimize the ulcerogenic potential of NSAIDs. Two major drugs were produced by this approach: celecoxib10 (Figure 2, structure 19), and rofecoxib11 (Figure 2, structure 20). The subtype-COX-2 enzyme has a selective binding area for the sulfone group while the subtype-COX-1 lacks such an area.

6. NSAIDs and Blood Clotting

The inhibitory effects of NSAIDs on the production of prostacyclin (PGI) and thromboxane (TXA) have different effects on the blood clotting process. Inhibition of PGI production may promote blood clotting, while inhibition of TXA production may inhibit blood clotting. However, the effect of NSAIDs on blood clotting is useful for cardiovascular diseases such as strokes and heard attacks. Aspirin was found to decrease blood clotting by inhibiting the thromboxane production and through chemical acetylation of the blood platelets.

7. NSAIDs and Cancer Chemotherapy and Prevention

COX-2 inhibitors have recently emerged as a promising new class of drugs that may be useful for cancer chemotherapy and prevention.12 Celecoxib was reported to be useful in decreasing the risk of developing colorectal cancer for patients with familial adenomatous polyposis (FAP).13-15 A recent indicated a possible role of COX-2 inhibitors in breast cancer chemoprevention.16

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8. Summary and Conclusion

• The class of NSAID represents an important group of drugs indicated for treatment of inflammation. The drugs suppress inflammation through inhibiting prostaglandins synthesis.

• Chemistry and structure activity relationships of NSAID show that all members of the class have 2 basic chemical entities: an acidic functional group and a highly lipophilic tail.

• Most members of the class share similar kinetic properties of good absorption after oral administration and strong plasma protein binding. Phase-I metabolites are generally inactive as COX inhibitors except for the prodrugs: sulindac and nabumetone, where phase-I metabolism generates the active metabolites.

• All members of the class act by the same mechanism of action, reduction of prostaglandin synthesis through inhibition of the enzyme cyclooxygenase (COX). All members of the class possess antipyretic and analgesic properties; however, only those with strong inhibitory effects on PGs synthesis are useful as anti-inflammatory drugs.

• Most members of the class predispose for the development of peptic ulcer disease; hence, they are classified as ulserogenic agents (ulcer-causing drugs). Gastric ulceration is attributed to the inhibitory ef-fects of NSAIDs on prostaglandin synthesis and its subsequent inhibitory effects on mucin secretion.

• Due to the inhibitory effects on thromboxane (TXA2) biosynthesis, long term use of most of the class members results in decreased blood clotting, which can lead to serious bleeding problems if combined with the development of an ulcer.

• NSAIDs, especially selective COX-2 inhibitors, represent a new class of cancer chemotherapeutic and chemopreventive agents. Several members of the class were found to be promising in treatment and prevention of colon, breast, and bladder cancer.

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