Non-steroidal and anti-inflammatory drugs

Introduction

Non-steroidal and anti-inflammatory drugs are writing shortly as NSAID's. The mechanisms of these pain relieving drugs will be discussed as well as their side effects. The following drugs will also be discussed: aspirin, paracetamol and ibuprofen.

Mechanism of action of NSAID's

Most if the enzymatically active COX (cyclo-oxygenase) or prostaglandin endoperoxide synthase is found in large quantities in the endoplasmic reticulum of prostanoid-forming cells. These enzymes are membrane bound hemoglycoproteins and glycoproteins. The glycoproteins show enzymatic activities of COX. The COX enzyme exists as two isoforms COX-1 and COX-2 and these two COX enzymes perform the same activities but have a slight difference in the amino acid sequences. The COX enzymes can carry out two functions, of which the first function is known as the dioxygenase step. During the dioxygenase step two oxygen molecules is attached to the arachidonic sequence at specific carbon atoms, in this case carbon atom 11 and 15. As a result an endoperoxide intermediate is produced which is extremely unstable, this intermediate is called prostaglandin G2 (PGG2) and a hydroperoxy group is found at carbon atom 15. The second function is known as the peroxidase function, it is in this step where PGG2 is converted into prostaglandin H2 (PGH2), and again there is a group found at carbon atom 15, in this case it is a hydroxyl group. The active sites of the COX enzymes consist of a long hydrophobic channel and at the apex of these long hydrophobic active sites tyrosine-385 and serine-530 are situated. The inhibition by the NSAID does mostly occur during the dioxygenase step and it is usually competitive as well as reversible. However, unusual to other NSAID's aspirin is known for its characteristic to irreversibly inhibit COX-1 by acetylation of serine-530. Comparing the two COX enzymes, it is noticeable that the inhibition of COX-1 is rapid occurring whereas the inhibition of COX-2 is quite slow and as well as irreversible. NSAID's inhibit COX enzymes by entering their hydrophobic channel, then form hydrogen bonds with arginine-120 and so prevent the enzyme specific substrate from binding to the hydrophobic channel.

As stated before COX-1 and COX-2 have similar activities, this means that they also have similar active sites for their natural substrates and for the inhibitory NSAID's substrates. Therefore COX-1 and COX-2 are quite similar in structure. COX-2 differs to COX-1 by its noticeable bulky side pocket, which is due to change of a single amino acid in the structure of its hydrophobic channel.

COX-1 has clear physiological functions, an example of which, the activation of it leads to prostacyclin production. The releasing of prostacyclin in the gastric mucosa provides the prostacyclin a characteristic of being cytoprotective. There is also the COX-2 enzyme, which is induced by flammatory stimuli and cytokines in migratory and other cells, so it is natural to say that the inhibition of the COX-2 enzyme is caused by the anti-inflammatory actions of NSAID's. In contrast, the inhibition of COX-1 enzymes will lead to the development of side-effects such as the irritation of the stomach lining.

Aspirin

Aspirin is described as a painkiller which has inflammatory effects. Aspirin is said to reduce the tendency of blood clotting, which is why it is a drug very useful in heart attacks and strokes. Aspirin is also a drug used in the condition "tendonitis", which is caused by the inflammation of a tendon. That is true because of the anti-inflammatory property of aspirin.

Mechanism of action of aspirin

Prostaglandins can be produced by both COX-1 and COX-2. The prostaglandins produced by COX-1 usually carry out functions such as the maintenance of the normal platelet activity or the protection of the stomach lining. The prostaglandins produced by COX-2 will be usually responsible for triggering pain and inflammation. The prostanoid produced by COX-1 enzyme is called thromboxane A2, and it is this that causes the aggregation of platelets. Aspirin is said to inhibit these enzymes, and by inhibiting COX-1, the production of thromboxane A2 is terminated and so the platelets lose their tendency to aggregate. The inhibition of COX-1 enzymes is ideally unwanted; however the inhibition of COX-2 enzyme tends to relieve pain and will lead to anti-inflammatory effects, which are the favourable effects of aspirin.

Anti-inflammatory effects

Drugs with anti-inflammatory properties have the ability to reduce oedema and the pain felt. This is achieved by NSAID's through their inhibiting ability of the COX enzymes that are produced at the injury site of skeletal muscles. The COX-2 enzyme will be accountable for the inflammatory effect and so the inhibition of this enzyme is known as the anti-inflammatory effect.

Antipyretic effect

Normal body temperature is controlled by a centre in the hypothalamus. When there is any irregular activity at this centre, the normal body temperature will change, and a fever will arise. In fevers NSAID's tend to operate in a way to restore the body temperature back to normal, however when the body temperature is set back to normal, they will not affect the body temperature any more.

The normal body temperature maybe be raised in the following manner: firstly an inflammatory reaction occurs, then during this reaction bacterial endotoxins stimulate the macrophages production from the pyrogenic interleukin-1, which then in turn stimulates the production of E-type prostaglandins that have an effect of increasing the normal body temperature. The antipyretic effect of NSAID's takes place in the hypothalamus and is especially known for its function to inhibit the production of prostaglandin. However there may be other mechanisms by which fevers may arise.

Analgesic effect

The analgesic effect of of NSAID's is to reduce the pain brought about by inflammation or tissue damage. This is accomplished by two different activities that occur to bring about the analgesic effect. Nociceptors are receptors stimulied by pain stimuli. On tissue damage bradykinin is released, this increases the sensitivity of the nociceptors. The first activity involves the reduction of prostaglandins, prostaglandins stimulate nociceptors, and therefore reduces the pain that is brought about in toothaches, arthritis and in other situations where prostaglandins are released locally in larger quantities than normal. NSAID's with analgesic effects can also relieve headaches. They do this by terminating the vasidilotary effect of prostaglandins in the brain. The second activity takes place in the spinal cord section of the CNS, and its function is to combine two or more neural impulses to trigger an action potential that is transferred from afferent pain fibres to intermediate neurons in the dorsal horn. This function can occur because inflammatory injuries to the living tissues enlarge the production of prostaglandin in the spinal cord.

The specific side effects concerning aspirin

Certain side effects are caused specifically by aspirin, for example salicylism or Reye's syndrome. The intake of excessive doses of salycilates causes the occurrence of salicylism, which can be identified by symptoms such as ear infections, wooziness, decreased hearing and even the occasional feeling of sickness and vomiting. Reye's syndrome rarely occurs in children. It is a disorder involving brain and nervous damages that occur as a result of liver disorders. It is usually followed up by an acute illness. The disruption of the oxidative phosphorylation caused by salicylates will result into an increase of oxygen consumption and therefore the production of CO2. The result of this will be respiration being affected, then in turn resulting into hyperventilation. The occurrence of hyperventilation will then be the cause for respiratory alkalosis which is made up for by the excessive removal of CO2. However on the application of larger doses of salicylates, the removal of CO2 may not be possible as the respiratory disruption may be too large, thus leading to a respiratory acidosis. Aspirin can also lead to hyperpyrexia and dehydration due to vomiting. Aspirin can also have some unfavourable effects on the CNS that can evolve to coma and respiratory disruption.

The non specific Side effects

Prostaglandins are involved in the gastric cytoprotection, renal vascular auto regulation, platelet aggregation and induction of labour and it is this that has lead to the expectation that all NSAID's will follow a pattern of mechanism dependent side effects to some degree. However it is possible that additional side effects may arise which do not follow a specific pattern of mechanisms.

The side effects include gastro-intestinal discomfort, nausea, diarrhoea, and the occurrence of occasional bleeding and ulceration. The damage that the NSAID's contribute to the gastro-intestine could be local as well as systemic. The most undesirable effects of NSAID's are the gastrointestinal events which are most common. This is said to be due to the inhibition of gastric COX-1, whose task is to synthesize prostaglandins.

The percentage of users of NSAID's suffering from gastrointestinal damages is an estimate of 34% to 46%, however, gastrointestinal damages may not be noticeable as the symptoms may lead to severe haemorrhage and/or perforation.

The inhibition of COX in the gastric mucosa affects the mechanism of action of the gastrointestinal damage and so this damage can be observed if the drugs are either orally or systematically applied. Selective inhibitors of COX-2 provide good treatments since they provide good inflammatory and analgesic actions with less gastric damages.

The inhibition of PGE2 and PGI2 production in the kidney could possibly be the cause of the build up of high blood pressure, consequently this can be related to the increased risk of cardiovascular diseases. Having said that, high blood pressure such as this, relies on the dosage as well as on time.

Other undesirable effects are rashes. Mild erythematous, urticarial and photosensitivity reactions are different examples of rashes. A more severe condition of a rash is the Stevens-Johnson syndrome which can be lethal. Acute renal insufficiency can also be caused by NSAID's and is mainly found in patients with susceptible renal function.

Paracetamol

Paracetamol is a drug that is famed for its excellent analgesic as well as antipyretic effect. However its anti-inflammatory effects are relatively weak therefore paracetamol does not give rise to gastric or platelet side effects. The existence of another isoform of COX, known as COX-3, explains the odd behaviour of paracetamol compared to the other NSAID's. COX-3 is said to have of existed in the CNS predominantly of other species and that drugs such as paracetamol selectively inhibit this enzyme.

Ibuprofen

Ibuprofen is defined as an NSAID that can bring about analgesic effects as well as antipyretic effects and is therefore used in the treatment of rheumatism and arthritis.

Ibuprofen also inhibits both COX enzymes, reducing the prostaglandin production, therefore reducing the thromboxane A2 production. The overall effect is then production of the antiplatelet effect.

Contra-indications

Besides the fact that NSAID's are mainly used to relieve pain, they can also present some side effects. To decrease the risk of side effects, caution should be taken when the drugs are given to an elderly patient. Caution should also be taken when the drug is to be taken by a patient suffering from allergic disorders, for instance asthma attacks, angioedema, urticaria, or rhinitis are examples of allergic reactions which could be caused by aspirin or any other NSAID's, during the pregnancy and breast-feeding period of a patient, and in patients suffering from coagulation defects. NSAID's are proved to be linked to the reduction in female fertility when used over a long period of time, however it is a reversible process which is achieved by terminating the treatment.

If a patient were to suffer from cardiovascular diseases in which the renal, cardiac or hepatic arteries are damaged, it will be required for one to be cautious when dealing with NSAID's as they can be harmful to the patient and may damage the renal functions. In fact, it is safe to say that all NSAID's are contra-indicated with severe heart failure. So it is necessary to keep the dosage of NSAID's as low as possible as well as to monitor the renal function.

Selective inhibitors of COX-2 show contra-indications in diseases such as ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, and moderate or severe heart failure. Therefore these selective inhibitors of COX-2 should be treated with care in patients with a history of cardiac failure, left ventricular dysfunction, and hypertension. Special care should also be taken in patients suffering from oedema and in patients that potentially could develop heart diseases.

Summary

To sum it all up aspirin, paracetamol and ibuprofen are all NSAID's. Aspirin and ibuprofen possess excellent anti-inflammatory, antipyretic and analgesic properties but paracetamol only possesses excellent antipyretic and analgesic properties but weak anti-inflammatory properties. Therefore paracetamol is sometimes not classsified as an NSAID at all. NSAID's inhibit COX enzymes. When COX-1 is inhibited, the release of prostaglandins will be reduced and therefore the cytoprotection of the gastric lining will be decreased as well as the platelet aggregation. This will lead to the development of side effects such as gastro-intestinal discomfort, nausea, diarrhoea, and the occurrence of occasional bleeding and ulceration. On the inhibition of COX-2 enzymes, the release of prostaglandins will be reduced and so this will result into the decrease of the pain felt or the inflammations. These are the desirable effects a NSAID may possess and an ideal NSAID will be one that only inhibits COX-2 enzymes.

References

Journals:

C:\Documents and Settings\Family F\My Documents\My Received Files\ScienceDirect - Thrombosis Research The mechanism of action of aspirin.mht

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TDC-3SY283K-2-5&_cdi=5195&_user=121744&_orig=search&_coverDate=03%2F30%2F1998&_sk=998959996.8998&view=c&wchp=dGLbVlW-zSkWb&md5=479a9eeedee0f4b73745af6526212705&ie=/sdarticle.pdf

http://jpet.aspetjournals.org/content/301/3/1126.full?sid=3305beb7-773f-4a6e-a802-bb0d92afb369

Web pages:

http://www.utahmountainbiking.com/firstaid/painmeds.htm#Aspirin (beneficial effects)

http://www.medicinenet.com/nonsteroidal_antiinflammatory_drugs/article.htm#what (nsaids)

http://www.medscape.com/viewarticle/506101_2 (aspirin mechanims of action)

http://www.fpnotebook.com/Pharm/Analgesic/Ibprfn.htm (ibuprofen)

http://www.faqs.org/sports-science/Mo-Pl/Nonsteroidal-Anti-Inflammatory-Drugs-NSAIDs.html (anti inflammatory effect)

Books:

Rang, H.P. et al., 2007, Rang and Dale's Pharmacology, 6th ed, Churchill Livingstone, p. 226-237

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