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Aspirin

Introduction

Aspirin is one of the world oldest non-steroidal anti inflammatory drugs (NSAID), and the therapeutic effects that it possesses seems to be endless, even today new advances are being made in medicine with this simple drug discovered one hundred and fifty years ago. This report aims to explore the uses of aspirin as a therapeutic drug by looking at the advantages and disadvantages it has on the body, in terms of what it cures and the side effects that it causes.

I will be looking at how aspirin is synthesised and the chemical properties that it possesses that make it such a versatile drug. In addition I will be looking at side effects caused by aspirin and other derivatives based on aspirins composition. Furthermore, this report will also explore the uses of aspirin that have been discovered in recent years, and the future of drug treatments that it has inspired.

Background / History

Aspirin was first discovered and synthesised by a French chemist named Charles Frederic Gerhardt in 1853. He accidentally stumbled upon one of the most widely used drugs to date while mixing acetyl chloride with a sodium salt of salicylic acid. An alternative synthesis method of aspirin was then found six years later that yielded an analytically purer form of acetylsalicylic acid (aspirin). The structure was unknown until 1969 when the different functional groups were assigned, an acetyl group connected to phenolic oxygen, which gave the chemical name of acetylsalicylic acid, shortened to aspirin.

In the first half of the twentieth century aspirin was the drug of choice millions of people. This was a direct result from its effect at curing the many people suffering from flu during 1918 Spanish flu pandemic. Its popularity decreased somewhat after the mid twentieth century when the synthesis of paracetamol and ibuprofen were discovered, as these were seen as better alternatives to the symptoms of flu and pain.

Chemistry and properties of Aspirin

Aspirin is a non steroidal anti inflammatory drug (NSAID) whose chemical name is acetylsalicylic acid, a derivative of salicylic acid which is one of the starting materials it is synthesised from. From formation it is a white crystalline powder which is stable in dry air but will eventually decompose in water, which is the reason the tablets are sold in air tight foil packets. The pKa for acetylsalicylic acid under standard conditions (298K 1atm) is 3.5, which shows that it is slightly acidic. Aspirin also exhibits polymorphism, the ability to form more than one crystalline structure. The pKa of acetylsalicylic acid means that it is a relatively weak acid and very little is ionised in the stomach.

Structure

From Fig 1 and Fig 2, it is clear to see that the structure of aspirin is not as complex as its modern day competitors, such as paracetamol. Its synthesis is also quite simple and is regularly conducted in undergraduate teaching labs. Acetylsalicylic acid is a benzoic acid with an ester group attach at the ortho site.

The mechanism / synthesis

The reaction that takes place to produce acetylsalicylic acid is esterification. Salicylic acid is treated with acetic anhydride to produce aspirin and a by product of acetic acid. An excess of protons is needed to drive the reaction forward and usually sulphuric or phosphoric acid is used as a catalyst in the reaction mechanism. The reaction is basic in principle; the phenol group of Salicylic acid is converted into an ester group (R-OH à R- OCOCH3).

The oxygen lone pair on the ortho OH group attaches the carbonyl carbon on the acetic anhydride. The C=O double bond breaks and reforms and kicks out the leaving group to form an acetate anion. This leaving group is fairly stable as the negative charge can be delocalised over both oxygens giving them partial double bond character. The final step is for the anion to remove the proton from the otho oxygen. The acid catalyst can also be used as a source of protons for this step and therefore lowering the activation energy of the reaction.

A sythesis from phenol is shown below, showing the different steps and reagents required to perform this experiment in an undergraduate laboratory.

Once aspirin is prepared it must be isolated from the by product of acetic acid, salicylic acid and the acid catalyst. The acetic acid is water soluble so the product is washed with cold water. In moist conditions aspirin can decompose to yield acetic acid and the starting material of Salicylic acid, and must therefore be isolated from air which contains moisture.

Traditional Treatments using Aspirin

Aspirin has been used for more than 100 year to relieve the symptoms of the common cold. However in it only in relatively recent years that other uses have "reinvented" aspirin as a staple drug in the commercial market. Aspirin can relive the symptoms of:

Moderate pain, headaches/ migraines, sore throats, tooth aches, period pains, and also systematic relief of influenza, fevers, colds, sprains, lumbago, fibrosis's, muscular aches and joint and swelling stiffness. Its versatility for such an array of different treatment has labelled it as a 'wonder drug'.

As well as this many doctors encourage people who have a higher risk of developing a cardiovascular disorder to take between 75-81mg of aspirin a day to lower that risk. This is due to aspirin having an anti platelet effect by inhibiting the thromboxane, a chemical that helps bind platelets together, an action used by the body to repair damaged blood vessels. This is the reason why a low dose of aspirin could benefit people at high risk to the formation of unwanted blood clots that lead to heart attacks and strokes.

However in a contradictory BBC News article Professor Colin Baigent, University of Oxford, stated "We don't have good evidence that people benefits from long-term aspirin intake as risk exceed the risks by an appropriate margin"[5]. The article contained statistics relating to a clinical trial conducted by the National Institute for health and Clinical Excellence (NICE), which did trials in healthy and high risk patients and found that there was no long term advantage for people to take aspirin due to the adverse side effects of the drug itself, a topic that this report will analyse in greater detail.

Although aspirin can conceal the symptoms of a cold it does little to prevent or cure infection. Its sole purpose is to relieve pain which can be deceptive. Dr John Mann states in his book that "The treatment for the common cold remains largely palliative rather than curative. Administration of anti-inflammatory agents like aspirin will relieve many of the symptoms without necessarily reducing the period of infection."[6] This can be quite dangerous as it doesn't always allow the person to know how ill they are and what are the limits they can push their body to.

Pharmacokinetics

Aspirins pKa, of 3.5, shows that it is much weaker than the acid found in the stomach and is therefore readily protonated, allowing its passage across the mucus and into the stomach. Due to the poor solubility of aspirin in acidic conditions the majority of absorption has to occur in the ileum due to its large surface area. The esterates in the plasma and tissues then hydrolyse aspirin, which yields salicylate acid, the compound which processes anti-inflammatory actions. The plasma half life of aspirin generally depends on the dosage, details of which are given in the book Pharmacology "The duration of action is not directly related to the plasma half life because of the irreversible nature of the action of acetylsalicylic acid and how it inhibits COX activity."[7] This reference also provides another key elemet which differs aspirin from its modern day rival drugs. The actions it possesses in the body are irreversible, which is not the case of paracetamol and ibuprofen.

COX1 and COX2 Inhibitors

Cylooxygenase (COX) is an enzyme in the body used to produce, prostaglandin, a chemical released by the body when it is hurt or in pain. It relays messages to the brain via the nerves system to induce pain and inflammation to the injured area. Aspirin is used to inhibit the COX enzymes and therefore reducing the levels of prostaglandin and in turn the pain or swelling in the area.

Aspirins effect at inhibiting COX enzymes is also the reason for its use at preventing heart attacks in high risk patients by acting as an anti platelet agent. This is due to prostaglandin providing a synthesis route for thromboxanes, which are the chemicals responsible for the aggregation of platelets that form blood clots, by what is effectively thinning the blood in the body, aspirin found its dual role in modern day medicine. This is the reason why many doctors encourage the regular taking of low doses of Aspirin for anyone who is prone to heart conditions. It is seen as a preventative drug for heart problems.

Chemistry of how it works

Side effect & disadvantages

Although aspirin has many uses to combat a range of different illnesses, it is still very much the topic of discussion for many doctors and scientists of whether the helping effects outweigh the side effects caused by aspirin. A starting point would be to mention that all drugs whether in the research process or commercially available produce unwanted side effects. Some of the side effects include "rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black or bloody stools; confusion; diarrhoea; dizziness; drowsiness; hearing loss; ringing in the ears; severe or persistent stomach pain; unusual bruising; vomiting"

Although there are many symptoms listed they are very uncommon to be suffered by the average person. The side effect of hypersensitivity is more pronounced in people who suffer from asthma. "Hypersensitivity side effects have included bronchospasm, rhinitis, conjunctivitis, urticaria, angioedema, and anaphylaxis. Approximately 10% to 30% of asthmatics are aspirin-sensitive (with the clinical triad of aspirin sensitivity, bronchial asthma, and nasal polyps). The mechanism of aspirin-induced hypersensitivity may be related to an up-regulation of the 5-lipoxygenase pathway of arachidonic acid metabolism with a resulting increase in the products of 5-lipoxygenase (such as leukotrienes)."[9] Therefore aspirin limits the amount of people who can benefit from its effects due to side reactions that occur in the body.

Furthermore, the taking of aspirin by children and adolescents to treat flu like symptoms is discouraged due to the risk of Reyes syndrome. This is a potentially fatal disease that causes the brain, liver and many other vital organs to deteriorate rapidly. The cause and mechanism of this illness are not known exactly but there has been a strong correlation between people who take aspirin and develop the disorder.

Although many people with heart conditions are urged to take aspirin, it can effect on the efficiency at which vaccines can work on the body. Charles Brown, associate professor of veterinary biology in the MU College of Veterinary Medicine states that "These drugs block the enzyme COX-1, which works in tissues throughout the body. We have found that if you block COX-1, you might be decreasing the amount of antibodies your body is producing, and you need high amounts of antibodies to be protected."[10] By effecting the way vaccines work on the body is very dangerous and this topic is therefore being looked at in much greater detail. Providing immunity from harmful diseases far outweighs the majority of treatments that a person would take aspirin for.

The Bright future of Aspirin

Researchers are now looking into the benefits aspirin has, not only in inflammation but also uses in cardiovascular disorders, colonic and rectal cancer treatment, Alzheimer's disease and radiation-induced diarrhoea.

The COX-2 enzymes are now thought to be related to certain cancers and abnormal growths in the intestinal tract. Research is being made in the ability of COX imbibing drugs, such as aspirin, to reduce the occurrence and growth rate of cancerous cells. COX-2 inhibitors are currently being studied in relation to breast cancer and their effect is thought to beneficial in the 'fight' against cancer.

Although aspirin is not being used as a drug to treat cancer, its effects are the same, in which it inhibits COX-1 and COX-2 enzymes. A publication from the U.S. National Library of medicine and Health states "A number of mechanisms have been proposed to explain the anomalous effects of aspirin. The first of these relates to the unique mode of action of aspirin, which acetylates the COX-2 enzyme and generates the cancer-suppressing 15R-hydroxyeicosatetraenoic acid at the site of a potential tumour. The alternative rationale relates to the metabolism of aspirin to salicylic acid, which has a cyclooxygenase independent anti-inflammatory mechanism, preventing the inflammatory response at the gene transcription level."[11] As COX enzymes are now being looked at in more detail in relation to cancer growths, the subject of aspirin and its inhibition are inspiring new developments in this field. The main aim of these new drugs is to improve on the therapeutic index of aspirin by modifications. Therapies such as sulindac and celecoxib are derivatives that have been inspired by aspirin.

There are also experimental clinical trials currently taking place with regards to Alzheimer's disease, although this is still very much a topical debate between medical practitioners. The reason for this effect is that the brain tissue of people with Alzheimer's contains extracellular amyloid plaques which are produced via inflammation. By taking a low does of aspirin regularly and inhibiting the production of prostaglandins, and therefore inflammation, it may be possible to prevent cognitive decline. Other evidence supporting the theory of aspirin reducing Alzheimer's is that it inhibits that activity of beta amyloid-42 peptide, the principal component of the amyloid plaques. Although the evidence is compelling, there is still not enough to support either of these theories and the results of clinical trails are still being awaited.

Conclusion

This report has shown that aspirin can be used to treat a very wise variety of illnesses and diseases. Even today, over a century after its discovery, new uses are being formulated with the mechanisms and reactions that occur with aspirin in the human body.

As shown in this report the number of disadvantages and side effects of aspirin are almost as great as its therapeutic uses.

I do however believe that with the clinical trials of diseases such as cancer and Alzheimer's, aspirin has cemented its place in history as truly 'a drug for all ills'.

Aspirin is the world's oldest non steroidal anti-inflammatory drug still in use today. The reason for aspirins abundant success is its ability to "cure" almost anything. It has proved in medicine to be a very versatile and comprehensive drug of choice. Even today, two centuries after its synthesis, new uses for it are still being discovered and investigated. It also helped open a lot of doors in pharmaceuticals with the many derivatives that have come from it, including paracetamol.

The side effects that its yields are almost as plenty as the ailments that it cures and with the growing technological advances I am sure a new advance will be made to replace aspirin as the worlds drug of choice. It h

References List

Websites

Google images [online]. [Assessed 20th October 2009]Available from:http://www.3dchem.com/imagesofmolecules/Aspirin.jpg

Google images [online]. [Assessed 20th October 2009]Available from: http://www.edinformatics.com/interactivemolecules/3D/aspirinstr ucture.jpg

Electrophilic Substitution of the Phenol Aromatic Ring [online]. [Assessed 18th November 2009] Available from: http://www.cem.msu.edu/~reusch/VirtualText/Images2/phenlsub.gif

Google images [online]. [Assessed 27th October 2009]Available from: http://www.jci.org/articles/view/13375/files/JCI0113375.f1/medium

Aspirin 'only for heart patients' [online]. 2009 [Assessed 25th October 2009] Available from: http://news.bbc.co.uk/1/hi/8338763.stm

"WIKIPEDIA CONTRIBUTERS" Aspirin [online]. 2009 [Assessed 25th October 2009] Available from: http://en.wikipedia.org/wiki/Aspirin

WOLTERS, K. Aspirin side effects[online]. 2009 [Assessed 7th November 2009] Available from: http://www.drugs.com/sfx/aspirin-side-effects.html

The synthesis of aspirin [online][Assessed 19th November 2009] Available from: http://wwwchem.csustan.edu/consumer/aspirincons/aspirincons.htm

GARDINER P.S. The medicinal chemistry implications of the anticancer effects of aspirin and other NSAIDs [online]. 2009.[Assessed 3rd December 2009] Available from: http://www.ncbi.nlm.nih.gov/pubmed/12769697

UNIVERSITY OF MISSURI COLUMBIA Missouri scientists discover aspirin and Tylenol can inhibit vaccine efficacy [online]. 2003.[Assessed 22nd November 2009] Available from: http://www.news-medical.net/news/20091201/Missouri-scientists-discover-aspirin-and-Tylenol-can-inhibit-vaccine-efficacy.aspx

Books

John Man (2004) Life Saving Drugs 3rd ed. RSC

Rang H.P & Dales M. (2007) Pharmacolology 6th ed. Churchill Livingstone

K.D Rainsford (2004) Aspirin and related drugs 1st ed. CRC Press

Murray J. (2000) Organic Chemistry 5th ed. Thompson Learning

K.D. Rainsford (1984) Aspirin and the Salicylates 1st ed. Butterworths

M. Pairet and J. van Ryn (2004) COX-2 Inhibitors 5th ed. Birkhauser

Journals / periodicals

* RIDKER P., CUSHMAN M., STAMPFER M. Inflammation, Aspirin, and the Risk of Cardiovascular Disease in Apparently Healthy Men, April 3rd 1997, Volume 336, page 973-979 [assessed 16th November 2009]

* HENNEKENS C., TRACY R., Parkinson's disease (PD) is a neurodegenerative disorder, 2003, Issue 9, Page 5473-5478. [assessed 17th November 2009]

* THUN MJ, NAMBOODIRI MM & HEATH CW Aspirin use and reduced risk of fatal colon cancer [online], 1991, Volume 325, pages 1593-1596,[assessed 5th December 2009]. Availiable from: http://content.nejm.org/cgi/content/abstract/325/23/1593

· STEWART W, KAWAS C, CORRADA M, METTER J. Risk of Alzheimer's disease and duration of NSAID use, [online], 1997, Volume 48, pages 626-632 ,[assessed 5th December 2009]. Availiable from: http://www.neurology.org/cgi/content/abstract/48/3/626

Evaluation of references

The websites used in this report were found in arrange of places. The websites that were taken from Google have just been used as background or initial reading and have not been used to generate ideas that have been used in this report. Other websites search engines included Google Scholar which have been proof read by other leading researchers in that field. I have also used websites that have been quoted in articles and tried to evaluate how 'trustworthy' a source was. I have used some of the concepts I found in websites but have referenced accordingly.

The books used in this report have been written by people who are experts in their field and have been used as a source of reference in other articles related to this topic. Although they didn't give much in the way of new ideas or concepts, they were an excellent reference source for facts and also as a means of checking the accuracy of background information found on the internet.

The journal articles were very useful as they conducted research trails in relation to aspirin and different areas of the body. They posed a useful purpose in arguing a point of the effects of aspirin and then quoting a medical trail where it has worked. The journal articles did not state many facts as were used in books and websites, but introduced concepts and trails and the future of treatments which greatly aided my report.

There were no conflicting pieces of information in my source which shows that the information presented is accurate. The only source of conflict is general opinion and not on the effects or way in which aspirin actually works.

Before starting this essay I did not have a very clear idea on the theory used in this essay and most facts and ideas have been reworded from my source list. If I did not use a direct reference from a source I have quoted it in the overall reference list at the end as I may have used ideas or key concepts in the report.

11

[1]http://www.edinformatics.com/interactive_molecules/3D/aspirin_structure.jpg

[2]http://www.3dchem.com/imagesofmolecules/Aspirin.jpg

[3]http://www.cem.msu.edu/~reusch/VirtualText/Images2/phenlsub.gif

[4]http://www.cem.msu.edu/~reusch/VirtualText/Images2/phenlsub.gif

[5]http://news.bbc.co.uk/1/hi/8338763.stm

[6] John Man (2004) Life Saving Drugs 3rd ed. RSC

[7] Rang H.P & Dales M. (2007) Pharmacolology 6th ed. Churchill Livingstone

[8]http://www.jci.org/articles/view/13375/files/JCI0113375.f1/medium

[9]http://www.drugs.com/sfx/aspirin-side-effects.html

[10]http://www.news-medical.net/news/20091201/Missouri-scientists-discover-aspirin-and-Tylenol-can-inhibit-vaccine-efficacy.aspx

[11]http://www.ncbi.nlm.nih.gov/pubmed/12769697