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The aim of this dissertation is to research and write about the pharmacodynamics and pharmacokinetics of anti- inflammatory drugs. The mechanism and intended mode of action will also be researched as well as the potential cost of the drug to an individual and to society. These areas will be discussed in detail and will be concluded at the end of the dissertation.
To understand why anti-inflammatory drugs are taken to relieve symptoms of pain it is best to first discuss what pain actually is.
Pain is a feeling that causes discomfort and is uncomfortable. It is a way of the body sending signals to your brain to indicate something is not right within the body. Pain is classified on its duration and pathophysiology. Acute pain lasts for less time than chronic pain however it can still be present for up to six months. Common sources of acute pain are surgery, menstrual cramps or labour. Chronic pain is a persistent pain that will not go away despite injuries or wounds having healed. Common sources of chronic pain are back pain, headaches, arthritis or cancer pains.
Nociceptive pain occurs when there is damage to a tissue. Musculoskeletal disorders are known as nociceptive pain. Neuropathic pain arises from damage to nerves, brain, or spinal cord. Shingles is an example of neuropathic pain.
What are anti-inflammatory drugs?
Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat a variety of symptoms and conditions such as headaches, muscle sprains, fever and inflammation. They can be taken orally which is the most common method as they can be bought over-the-counter, no prescription is needed. They are also cheap and convenient. NSAIDs can also be given intravenously, rectally, and in an eye drop. Topical NSAIDs can also be used in the form of creams and gels which are applied directly onto the skin. There are many different types of anti-inflammatory drugs but the most common types are aspirin, ibuprofen and naproxen.
What are the side effects of NSAIDs?
The most common side effects of NSAIDs are
However, more serious side effects can occur from long term use such as
Fluid retention leading to Edema (swelling in body tissues)
Prolong bleeding after a surgery
What is the mode of action of Anti-inflammatory drugs?
The mode of action of NSAIDs is to block prostaglandin production by binding and inhibiting cyclooxygenase.
What are prostaglandins?
Prostaglandin is a fatty acid molecule produced from arachidonic acid. It is found in all cell membranes and is generated by lysosomal enzymes of neutrophils and other cell types. Prostaglandins belong to a group known as prostanoids. They have a variety of important functions within the body:-
Regulate transport of ions and water in the kidney
Involved in apoptosis(programmed cell death) and cell differentiation
Regulate relaxation and/or contraction of smooth muscles
Regulate blood pressure
Protect the stomach lining
Because prostaglandins help to protect the stomach lining, prolonged use of NSAIDs can cause several problems. Prostaglandins protect it by vasodilation of the gastric mucosa cells causing increased secretion of mucus and buffers. This is because the NSAIDs are designed to block the production of prostaglandins therefore the stomach lining is not being protected by the prostaglandin because it is not being produced. This can lead to ulcers and bleeding.
Another important function of prostaglandin is that they promote pain and fever hence the reason why NSAIDs are produced to block the production of them.
What is cyclooxygenase(COX)?
COX is an enzyme that is accountable for the production of the prostanoids. During research it was found that there are actually two different forms of cyclooxygenase known as COX-1 AND COX-2. COX is found in most tissues within the body. It is involved with converting fatty acids and turning them into prostaglandins. Arachidonic Acid is an example of a fatty acid. It is converted by COX to Prostaglandin H2. NSAIDs work by disturbing the cyclooxygenase pathway. So in order to understand this, firstly the pathway of cyclooxygenase should be researched.
Above, is a diagram showing the pathways of COX 1 & 2. COX 1 is a constitutive enzyme found in many mammalian cells. It is known as constitutive because the concentration of the enzyme in the body remains the same. It has many physiological functions such as protection of the gastric lining. This is because gastric mucosa cells produce prostaglandins through the COX-1 pathway. This pathway leads to GI side effects.
COX-2 pathway is known as being inducible and pathological. It is expressed more during inflammation, particularly in the kidneys, bone, female reproductive system and the brain. This pathway has fewer GI side effects. However there is an increased risk of cardiovascular side effects. This pathway causes fever and pain in the inflammatory response.
COX 1 AND 2 Inhibitors.
Traditional NSAIDs such as Ibuprofen and aspirin are known as 'non selective'. This is because they block the COX 1 pathway AND the COX 2 pathway. NSAIDs that only block the COX-2 pathway have less risk of causing damage to the stomach because the enzyme is not found in the stomach therefore the protection of the stomach is not compromised.
NSAIDs and Pregnancy.
Studies have shown that an increased risk of pulmonary hypertension in babies that are born due to expectant mothers using NSAIDs. Because NSAIDs can be so easily bought over-the-counter many expectant mothers do not realise that potential fatal risk that taking this medication could have on the newborn child, especially if taken in their last trimester. As discussed previously, NSAIDs block the synthesis of the prostaglandins. In expectant mothers, prostaglandins keep the blood vessel that carries blood from the mother's lungs to the foetus open. However, the prostaglandin synthesis will be inhibited by the use of NSAIDs which will close this blood vessel which can then lead to pulmonary hypertension. Some studies have showed that there could be a link between miscarriage and the use of NSAIDs however more research is needed to be able to say for sure if NSAIDs can cause miscarriages.
NSAIDs and Asthma
Aspirin-induced asthma is a subtype of asthma and can occur up to three hours after taking an aspirin. Although it is named 'aspirin-induced asthma,' other NSAIDs can cause an asthma attack. It is then followed by facial flushing, sneezing and rhinorrhoea. Rhinorrhoea is an inflammation of the lining of the nose which often results in a nasal discharge. People who take aspirin or an NSAID and have these symptoms may not even realise that they have intolerance to aspirin.
Figure 2 shows the mechanism of aspirin induced asthma. NSAIDs block the synthesis of prostaglandins as mentioned previously. In cases of those who suffer from asthma, it is the prostaglandin E2 which is blocked by the consumption of NSAIDs. This prostaglandin maintains normal body function but because it is reduced by the NSAID, increased amounts of the inflammatory mediator called leukotrienes are produced which lead to asthma attacks.
NSAIDs and Heart Failure.
Studies have shown that there is a link between taking NSAIDs and heart disease. However another study found that naproxen has increased cardiovascular safety than other NSAIDs such as Diclofenac and Ibuprofen.
NSAIDs and Rheumatoid Arthritis.
Rheumatoid Arthritis is an incurable autoimmune disease. An autoimmune disease is where the body's immune system attacks tissues within the body. Rheumatoid Arthritis is a progressive illness leaving the patient disabled. It also causes severe inflammation to joins, therefore NSAIDs are used.
Aspirin is not usually used to treat the pain caused by inflammation of the joints mainly because a high dose would be needed and because that will therefore increase the risk to the stomach. COX-2 inhibitors are primarily used for Rheumatoid Arthritis such as Naproxen, Diclofenac and Ibuprofen.
After researching the uses and effects NSAIDs has on the body, many scientists in many articles I read questioned whether they should be taken off the market because of risks posed with consumption. I do not think they should be taken off the market. Although it has been shown that they do cause ulceration and or bleeding in the stomach through prolonged use, they help significantly to relieve minor pains such as headache, sprains and strains. Pharmaceutical companies make a lot of money for selling NSAIDs over-the-counter so I do not think they would ever be taken off the market. However, the serious health risks that can affect the body over prolonged use needs to be more available. It does state these health risks in the leaflet that is provided when NSAIDs are purchased but how many people actually read it? And the question also has to be raised- how much is treating patients with severe illnesses associated prolong use of NSAIDs actually costing the NHS and ultimately the society? If these drugs were not available over-the-counter and only prescribed, then better monitoring of patients who were taking them could be in place to try to prevent serious illnesses occurring in the first place. But it all comes down to money. Pharmaceutical companies make millions over a year with the selling of NSAIDs over-the-counter. NSAIDs are also very much in public demand. Millions of people worldwide will take NSAIDs to get rid of a headache and other minor pains. They are so readily available and relatively cheap and also work on the pain! More studies and research is definitely needed to show if and how NSAIDs affect patients with underlying illnesses. A definitive link is needed with NSAIDs in relation to heart diseases. There is no answer as of yet. Studies have shown that there is an increased of heart disease with use of NSAIDs and other studies have shown that there is no link?
NSAIDs, could in the future, be used in treatment for many conditions such as breast cancer. They have the potential to be developed into a drug that is used for more than it is now.