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NSAIDs are a class of drugs that act to inhibit the activity associated with the COX enzymes. They act to disrupt the normal activity of the COX enzyme in order to achieve their therapeutic effects. As a result of this disruption of normal activity this leads to the undesired gastrointestinal side effects. The main affects which are achieved from the disruption are anti-inflammatory, analgesic and antipyretic.
Each NSAID is different both structurally and chemically therefore the nature of the NSAID depends on their mechanism and duration of action. This would be whether the drug acts non-selectively inhibiting both COX-1 and COX-2 pathways like aspirin, or like celecoxib which specifically inhibits only the COX-2 enzymes. The processes of inhibition can also depend on the type of NSAID used; it can be either reversible in the case of ibuprofen or irreversible in the case of aspirin. So the type of NSAID that is used is an important factor that needs to be considered before administrating the drug to the patient. Each drug has side effects associated with it and is contraindicated in certain people as it would provide more of a risk than a benefit if it was administered to certain patients.
Non Steroidal Anti Inflammatory Drugs (NSAIDs) have 3 main therapeutic effects which are:
These main affects are achieved by the mechanism of action that the NSAIDs have on their target the Cyclo-Oxygenase (COX) enzymes. This is due to the inhibition of Prostaglandins and Thromboxanes which are synthesised by the COX enzyme. These act as potent mediators of inflammation which are specific for the tissues in which they are located, produced and carry out their desire effect.
There are different Iso-forms of the COX enzymes the COX-1 and COX-2. They act to convert the substrate which is 20 carbon unsaturated fatty acid derivative known as arachidonic acid into prostaglandins and thromboxanes.
Each individual PG and TX has its own specific role and function where it is found in the body. For example in the hypothalamus PGE2 regulates the control of body temperature whilst in the stomach it is responsible for the protection of the gastrointestinal tract.
This following picture shows the various different types of prostaglandin and thromboxanes that are produced in tissues. Each one originally derived from arachidonic acid but is specific in both structure and function.
Image2 adapted from http://www.inra.fr/theses/these-integrale/Theses/gnadig/html/images/figure7.gif
The number in the subscript at the end of each prostaglandin and thromboxane refers to the number of unsaturated carbon double bonds in the structure.
The COX-1 enzyme is mainly responsible for the production of prostaglandins which act to coat the lining of the stomach with mucus. By doing this it carries out a secretary function protecting the stomach lining.
It also acts to aid with the aggregation of platelets in the blood.
As well as having many other functions depending on where they are present in the body.
The COX-2 enzyme is responsible for producing the inflammatory action. This is due to the production of prostaglandins which are the potent mediators of inflammation and are responsible for carrying out 3 key biological roles:
Increasing the sensitivity of the receptors in the skin causing pain.
Increasing body temperature through control of the hypothalamus in the brain.
To recruit inflammatory cells specifically to where they are needed in the body.
(Kourosh Saeb-Parsy et al 1999)
Aspirin comes from a class of drugs known as salicylates. It works by irreversibly inactivating both the COX-1 and COX-2 enzymes. This is done by the acetylation of a serine residue in the active sites of both the COX isoforms.
In the COX-1 enzyme active site the serine residue at the 530 position is acetylated.
In the COX-2 enzyme active site the serine residue at the 516 position is acetylated.
The mechanism of action in which aspirin has on the COX enzyme is show by the diagram.
Image 4: http://www.sciencemag.org/cgi/content/full/sci;280/5367/1268
This diagram shows how specifically the serine residue in the chain is acetylated
Image 5: Drawn on Chem Draw Ultra 11.0
By doing this the COX enzymes are no longer suitable for their function. The production of prostaglandins and thromboxanes is therefore inhibited by the COX enzyme. As the reaction of aspirin with the COX enzyme is irreversible therefore the duration of action depends on the ability of the tissue to re-synthesise new COX enzyme.
The inhibition of the COX-1 enzyme inhibits the production of prostaglandins which therefore stops the clumping together of platelets in the blood. This acts to reduce blood clot formation.
As the COX-1 enzyme is inhibited the primary function is also inhibited which leads to no production of the protective prostaglandins PGE2 and PGI2 which would act to protect the lining of the stomach. This would lead to the undesired gastrointestinal side effects which are stomach irritation and perforation of the lining of the stomach which would ultimately lead to ulcer formation and eventually bleeding.
In the COX-2 enzyme the inhibition of the prostaglandins is responsible for the beneficial effects which are:
To act as an anti-inflammatory by reducing inflammation and swelling.
To act as an analgesic by reducing the mild pain associated with inflammation.
To act as an antipyretic by reducing body temperature back to its original set point only. This is only if the rise in body temperature is due to a condition associated with a pathological condition. This is achieved by inhibiting the synthesis of the prostaglandins in the hypothalamus. By doing so this affect is carried out through sweating and vasodilation of the peripheral blood vessels.
Aspirin can be used as an over the counter analgesic. This is for the reduction of mild to moderate muscular skeletal or post operative pain. This is advantageous as it does not cause dependence which is usually seen with opioid medications.
Aspirin is used clinically in low doses for patients who are at high risk for problems such as:
The formation of blood clots. There are two different types of blood clots the first is a thrombus which is the aggregation of platelets causing a blockage at a specific point in a blood vessel. The second is an embolism which is the aggregation of platelets which started initially as a thrombus but broke off from a lage blood vessel and travelled through the blood where it causes a blockage in a smaller blood vessel.
Cardio vascular diseases such as a myocardial Infarction or Angina. These are due to an interruption or lack of blood supply to the heart muscle which could ultimately result in the death of a specific area of the heart muscle. Therefore it is used as a preventative measure to reduce the risk and to prevent any problems from occurring initially.
Ischemic strokes which are cause by the blockage of a small blood vessel in the brain due to an embolism (blood clot) which deprives oxygen to that particular area of the brain. This would ultimately lead to a loss in the motor function in which the blood vessel feeds.
The re-occurrence of another myocardial infarction or other cardiovascular diseases which would lead to more damage.
These problems are high risk because they affect the major organs of the body being both the heart and the brain. If untreated then these would ultimately result in tissue death due to the significant decrease in the blood flow.
Aspirin like any other drugs has contraindications which are certain situations were the drug treatment is not suitable for the patient because it has been proven to be more harmful than beneficial to the patient. The type of patients in which aspirin should not be administered to:
Patients with blood disorders such as aplastic anaemia and Haemophilia.
Aplastic anaemia is due to the bone marrow of the patient being unable to produce sufficient amount of blood cells. So the person has an initially low level of blood cells and platelets. If aspirin was administered to the patient they would be unable to replenish their bodies demand for the lost blood cells sufficiently both immediately and over a long period of time.
Haemophilia is due to either the lack of or the absence of a clotting factor which is responsible for the clotting of the blood. This would result in the patient requiring a longer time than usual to clot their blood in the case of a bleed. If aspirin was administered to the patient then they would take an even longer time to clot their blood by which they could effectively bleed to death.
Patients under the age of 16 as administration of aspirin in children is linked with a rare condition known as Reye's syndrome.
Patients who are currently on anticoagulant medications such as Warfarin. As they are specifically designed to increase the risk of bleeding so if aspirin was administered to the patient it would act to effectively thin the blood by preventing platelet aggregation. The potential hazard if both the drugs were administered together would result in the patient potentially bleeding to death.
Patients currently on any other medications such as prescription, herbal or even other NSAIDs as they could potentially interact together.
Patients who are asthmatics, currently breast feeding or on any other medications such as prescription, herbal or even other NSAIDs.
Patients who are allergic to any of the NSAIDs
Patients with gout as it can intensify their symptoms.
These contraindications of aspirin are due to the mechanism of action that it has on the COX enzymes. So interactions between different types of drugs need to be considered before administration.
(Rang and Dales 2007)
The common side effects of Aspirin are its ability to form ulcers due to the inhibition of the COX-1 enzyme. Aspirin is therefore best taken on a full stomach because it will become dispersed with the food present in the stomach and will also act rapidly. If it were taken on an empty stomach it will increase the risk of producing ulcers. Aspirin is not advised to be used over a long period of time as it can lead to Hepatotoxicity. This is the irreversible damage of the liver and kidney due to the excessive intake.
The other side effects associated with other NSAIDS are:
Tinnitus (ringing in the ears)
An alternative drug to aspirin is Ibuprofen. This is another NSAID which comes from a class of drugs known as propionic acid derivatives. It's mechanism of action is similar to aspirin because it also acts as a non-selective inhibitor of both the COX enzymes. Its main difference is that Ibuprofen acts as a reversible inhibitor whilst aspirin is an irreversible inhibitor.
Image 6: Drawn on Chem Draw Ultra 11.0
As the reaction is reversible the dosage administered to the patient affects the duration of action of the drug. If used in low doses it has fewer side effects than other non-selective NSAIDs but as a result its anti-inflammatory properties are also weaker. Its antiplatelet activity is mild and short compared to aspirin. As ibuprofen is not associated with Reye's syndrome it therefore can be administered to children.
The inhibition of the COX-1 enzyme cause the undesired adverse side effects associated with aspirin whilst the inhibition of the COX-2 is responsible for the major therapeutic effects. So a selective inhibition of only the COX-2 enzyme would therefore achieve the therapeutic effects whilst eliminating the adverse side effects associated with the inhibition of COX-1 enzyme.
This is the case with new NSAIDs such as Celecoxib. This comes from a class of new drugs know as COX-2 inhibitors. Celecoxib is a specific COX-2 inhibitor and at therapeutic concentrations it has little or no inhibitory effect on the COX-1 enzyme. This type of specificity is advantageous as it does not interfere with the COX-1 enzyme therefore it does not cause peptic ulcers as it has no effect on the gastric secretions in the stomach.
Image 7: Drawn on Chem Draw Ultra 11.0
(Rang and Dales 2007) (Gailbraith et al 2007)
COX-2 inhibitors are used to help relieve inflammation and musculoskeletal pain. These types of drugs are contraindicated in patients with a history of peptic ulcers, bleeding and liver disorders.
The main side effects of COX-2 inhibitors which are different from general NSAIDs are:
An increased risk of a stroke and cardiovascular diseases
Another NSAID that can be used is Paracetamol. It is used as a non-opioid analgesic (mild pain killer) which also reduces the body temperature when it is slightly high in the case of a fever. Paracetamol is different when compared with other NSAIDs as it does not trigger an anti-inflammatory response.
Image 8: Drawn on Chem Draw Ultra 11.0
Paracetamol does not cause the unwanted gastrointestinal side effects associated with the inhibition of the COX-1 enzyme. It also does not cause any significant amount of anti-inflammatory or antiplatelet activity which is associated with the inhibition of the COX-2 enzyme.
Paracetamol does cause an antipyretic activity which is believed to be associated with the inhibition of a COX-3 iso-enzyme which is present in the brain and spinal chord. This means that paracetamol acts to selectively inhibit the synthesis of prostaglandins only in the central nervous system.
It can be used as a mild analgesic to reduce mild pain in both children and the elderly. This is because in children it is not associated with Reye's syndrome and for the elderly it does not cause the unwanted gastrointestinal side effects which are due the inhibition of the COX-1 enzyme with other NSAIDs such as aspirin. To ensure a fast action mechanism paracetamol is best taken on an empty stomach as the presence of food would lead to a slower rate of absorption.
Paracetamol is one of the most dangerous NSAIDs if it is taken in excess. This is because it has the potential side effect of an overdose therefore should not be taken if the patient is on any other medications which contains paracetamol. This is due to the saturation of the liver enzymes which catalyse the paracetamol. This would result in the paracetamol being metabolised by another set of enzymes known as the mixed function oxidases. This metabolism pathway results in the formation of the toxic metabolite known as N-acetyl-p-benzoquinone. This metabolite would accumulate in the liver up to a point where it would result in necrosis which is a death of the resulting tissue. This type of damage to the liver is known as hepatotoxicity.
The side effects of paracetamol are rare compared to other NSAIDs because it doesn't affect the activity of the COX-1 or COX-2 enzymes. Its reported side effects are rashes, hypertension and renal damage which would be due to an overdose.
BNF 57 March 2009
(Gailbraith et al 2007)
The type of NSAID administered to the patient depends on what symptoms and conditions the patient is representing. As with each drug there is a slightly different therapeutic effect, side effect and contraindications. For these reasons the type of NSAID would be different for different types of patients.
As aspirin is used clinically in patients to reduce the risk of a myocardial infarction due to its antiplatelet properties. It also acts as well as acting as an analgesic and an anti-inflammatory but is contraindicated in children due to the link with Reyes Syndrome.
Ibuprofen carries out the same therapeutic effect as aspirin but at a much weaker level with its antiplatelet properties being mild and short lived when compared with aspirin.
Celecoxib overcomes the problem of gastrointestinal side effects associated with the inhibition of the COX-1 enzyme by acting as a selective inhibitor for the COX-2 enzyme. This can cause an increase in the risk of a stroke and cardiovascular diseases such as a myocardial infarction.
Paracetamol is specific as it acts to inhibit only the COX-3 enzyme and produces an antipyretic effect. As it inhibits the COX-3 enzyme it does not have any gastrointestinal side effects that are associated with the inhibition of the COX-1 enzyme with aspirin and can be used in children.
A combination of low dose NSAIDs can be used as a form of treatment for patients. This would include a selective COX-2 inhibitor and aspirin. As the COX-2 inhibitor would be responsible more the major therapeutic effect whilst its side effects overcome by the mechanism of action of aspirin. This combination could provide a higher therapeutic effect than if the drugs were administered alone.
Pharmaceutical Journal 2005 Volume 275; Issue 436
So the administration of a NSAID needs to consider many different factors ranging from age, gender, health to the ability to cope with the potential side effects that may arise due to taking the drug. This is because each patient has different tolerances to drugs. So the drug needs to be specific to meet the individual demands of the patient.
References using the Harvard Referencing System
Bibliography - Referencing using the Harvard Referencing System.
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: Galbraith A, Bullock S, Manias E, Hunt B, Richards A, (2007) 2nd Edition, Fundamentals of
Pharmacology Pages 271-273, 381-387, 465-471
: Patrick. Graham L, 2009, 4th Edition An introduction to medicinal chemistry Page 219
: Rang, H.P, Dales, M.M, Ritter, J.M, Flower, R.J, 2007 6th Edition Pharmacology Pages 215-238
: Saeb-Parsy. Kourosh. Assomull. Ravi, Khan, Fakhar Z, Saeb-Parsy Kasara and Kelly, Eamonn
(1999) 1st Edition, Instant Pharmacology Pages 107 - 110
Image 2 : adapted from http://www.inra.fr/theses/these-integrale/Theses/gnadig/html/images/figure7.gif
Image 3 : http://www.chiro.org/LINKS/DISCONTINUED/stovitz1.gif
Image 4: http://www.sciencemag.org/cgi/content/full/sci;280/5367/1268
Image 5-8: Drawn on Chem Draw Ultra 11.0
: Pharmaceutical Journal 2005 Volume 275; Issue 436