The worldwide market for NSAIDS is currently $9 Billion a year. NSAIDS are a class of drugs used by millions every day to reduce pain and swelling. Patients' response to NSAIDS and tolerance to them is variable; hence it is best to try several products to determine one with the best efficacy and tolerability for the patient. The basis for this remains unclear but is more likely to be related to disease activity compared to pharmacokinetics or anti-PG activity.
In single doses NSAIDS are said to have an analgesic activity, and in regular full doses have a lasting analgesic and anti-inflammatory effect that makes them useful for continuous treatment of inflammation. NSAIDS are used to heal pain and stiffness resulting from inflammatory rheumatic disease. In addition to this they reduce inflammation when used over a period of time.
Mode of action
Most of the effects of the drugs are believed to be related to the primary action of the drug. This usually involves inhibiting the fatty acid COX enzyme. Some of the NSAIDS such as aspirin, ibuprofen and indometacin inhibit the early steps in the prostaglandin biosynthetic pathway that transforms the unsaturated fatty acids into cyclic peroxides.
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There are three known isoforms of the fatty acid: COX-1, COX-2 and COX-3.
COX-1 and COX-2 are known to catalyse the same reaction but differences exist in the expression and role of each of the isoforms. COX-1 is expressed in most tissues and cells, and this includes blood platelets, and is believed to control synthesis of a host of fatty acids known as prostaglandins, that are responsible for cellular functions. Prostaglandins, derived from arachidonic acid by the action of prostaglandin synthatase (cyclooxgenase), are produced by the cells of the body and are released when cells are damaged, for example by invading micro organisms, tissues damage, allergy and other conditions. Prostaglandins play a variety of hormone-like roles; they are responsible for dilation of veins, inducing diuresis (increased excretion of urine) and muscle contraction.
On the other hand, COX-2 is present in the Central Nervous System; it is produced by many different cell types in response to trauma. COX-2 catalyses the production of prostaglandins such as PEG2, that help to increase the sensitivity of pain receptors on nerve endings and dilates blood vessels promoting pain, swelling and redness. It is induced in inflammatory cells when they are activated and hence is responsible for the production of prostanoid mediators of inflammation. NSAIDS are thus believed to be useful as they have the ability to block production of PEG-2. NSAIDS block the COX enzymes that are responsible for producing prostaglandins; as a result ongoing inflammation and fever are reduced. The protection of the stomach wall is reduced and this may lead to stomach ulcers.
MAJOR PHARMACOLOGICAL EFFECTS
NSAIDS have three major pharmacological desirable actions:
The body temperature is regulated by the processing centre in the brain known as hypothalamus. It does this by triggering changes to effectors, such as sweat glands and muscles controlling body hair. A fever is a result of the body becoming too hot and reverse of this is known as hypothermia, i.e. when the body temperature becomes too low. Once the temperature of the body has returned to normal, the temperature regulating mechanisms; sweating, vasodilation, then operate to reduce the temperature, in the case of a fever.
It must be concluded that NSAIDS play an important role in temperature regulation; by resetting the thermostat. They manage to do so by inhibiting the production of prostaglandin in the hypothalamus.
In addition to this, bacterial endotoxins are majorly responsible for the release of macrophages of a pyrogen that stimulates the generation of E type prostaglandins. These are known to raise the temperature set point.COX-2 is induced by IL-1 vascular endothelium in the hypothalamus and also plays a major role in regulating the temperature control.
NSAIDS are effective against mild or moderate pain, especially if arisen from inflammation or tissue damage. There are known to be two sites of action.
First, NSAIDS decrease the production of prostaglandins that sensitise nociceptors to inflammatory mediators. Hence, are effective in: arthritis, bursitis, pain of vascular origin, toothache, dysmenorrhoea, the pain of postpartum states and the pain of cancer metastases in bone, altogether, all conditions that are associated with increased local prostaglandin synthesis. Alongside, NSAIDS decrease post operative pain and are known to reduce the requirement of opiods by a third. The vasodilator effect of prostaglandins on cerebral vasculature is known to give the ability for relieving headaches.
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Second action of NSAIDS is in the spinal cord. There is an increase in the prostaglandin release within the cord due to inflammatory lesions and this in turn causes facilitation of transmission from afferent pain fibres to relay neurons in the dorsal horn.
One of the major side effects of analgesics is gastric irritation. The dose is taken after food. Enteric-coating involves covering the tablet core from disintegration in the acid environment of the stomach, to protect the stomach from the irritant affect of the drug. However, this process is slow acting and hence is unsuitable for a single dose of an analgesic.
Many mediators co-ordinate inflammatory and allergic reactions, and are produced in response to specific stimuli. The NSAIDS reduce the components of inflammatory and immune response in which prostaglandins, derived from COX-2 play a major part. These include: Oedema, Pain and vasodilation.
NSAIDS are known to suppress pain, swelling and increased blood flow associated with inflammation but have little or no effect on the progress of the underlying chronic disease itself. As a class they are without effect on other aspects of inflammation that contribute to tissue damage in chronic inflammatory conditions.
NON OPIOID ANALGESICS
This section involves a detailed discussion of the mode of action, specific effects and the side effects of two of the non opioid analgesics:
Aspirin also known as acetylsalicylic acid is the oldest known Non-Steroidal anti-inflammatory drug.
It is an analgesic, anti-pyretic and anti-inflammatory. Aspirin has an anti-platelet action that reduces clot formation. It is classified as a non-opioid drug that can be used for pain in musculoskeletal conditions. Is has also been indicated for treatment to symptoms such as headache, dysmenorrhoea and pyrexia.
MODE OF ACTION
Prostaglandins are formed in the body from unsaturated carboxylic acid. They are released from the tissues when it suffers diseases. This is to allow it to maintain its normal function and hence act to defend the cell against sudden change. Prostaglandins induce thickening of the blood. Aspirin reduces the stickiness of platelets in the blood so that they do not clump together and form clots. Aspirin is the most effective drug in the treatment of strokes.
Aspirin is a non selective inhibitor of both COX isoforms, it does so by irreversibly inhibiting COX, and hence platelet aggregation. Alongside, it inhibits pain stimuli at a subcortical site, thus being most effective in inhibiting pain both moderate and mild of inflammation.
Noticeably,Aspirin's antipyretic effect is mediated by the COX inhibition in the central nervous system and inhibition of interleukin-1 (that is released from macrophages during inflammation).
Aspirin is known to cause stomach and gut (gastro intestinal) side effects, such as ulcers and bleeding; hepatotoxicity, asthma, rashes, and renal toxicity. Some of the more common effects include being sick and indigestion.
With higher doses, patients tend to experience vomiting, tinnitus decreased hearing and vertigo. On the other hand, severe side effects may include swelling of the lips, mouth and throat, sudden skin rash, wheezing or breathing problems, in each case immediate action has to be taken.
It is also known as acetaminophen, and is used as one of the most common non-narcostic analgesic antipyretic agents.
Paracetamol has an excellent antipyretic and analgesic activity that allows inhibition of Central Nervous System prostaglandin synthesis however it is also known to have a weak anti-inflammatory activity. As a result, it is not responsible for gastric and platelet side effects like other NSAIDS. It is taken to relieve common aches pains including headache, muscle and joint pain, backache and period pain. It is also used to control a fever (pyrexia) when one has influenza. Brings down a high temperature caused by a cold flu, It works by blocking the way in which pain signals are processed in the brain.
Paracetamol can be given to children after they have had vaccinations to prevent a high temperature. When metaclopramide is co-prescribed, absorption of paracetamol is increased hence lower doses may be given.
MODE OF ACTION
Paracetamol is known to have another form of COX isoform (an alternate splice of COX-1), COX-3 that exists in the CNS and is a selective inhibitor of the enzyme cyclo-oxygenase. This differentiates Paracetamol from other NSAIDS .As a result causing lack of gastric ulceration and bleeding side effects symptoms like other NSAIDS. Paracetamol may help to protect from changes leading to hardening of the arteries. This is known to cause deaths from stroke and heart attack.
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With therapeutic doses, allergic skin reactions, rashes, blood disorders (that may include thrombocytopenia, leucopoenia, and neutropenia). Higher doses are known to cause kidney damage.
Toxic doses cause nausea and vomiting and after 24 to 48hours, potential fatal hepatotoxicity is observed. This happens when the liver enzymes, that catalyse the normal conjugation reactions are saturated, and cause the drug to be metabolised in place of the mixed function oxidases.N-acetyl-p-benzoquinone imine, toxic metabolite is inactivated by conjugation with glutathione. However once glutathione is depleted, the toxic intermediate accumulates, and reacts with nucleophilic constituents in the cell causing death of the tissues in the liver and kidney tubules.
In addition to this, agents such as acetylcysteine and oral methionine can prevent liver damage if given early.
It is one of the more commonly used NSAID. It is made from a compound: 2- (4- [2-methyl propyl] phenol) propanoic acid.
It has been the first and only modern NSAID available for oral use licensed for over-the-counter shelf. Is has anti-inflammatory (inflammation reducing), analgesic (pain relieving) and antipyretic (temperature reducing) properties. Hence, it is used primarily to treat the pain of rheumatism and other musculoskeletal disorders, moderate pain of inflammatory origin and postoperative pain.
MODE OF ACTION
Has an anti-platelet action that reduces clot formation. Its antipyretic action helps symptomatic relief of the fever associated with colds and flu. Administration can be oral or by topical application Ibuprofen is better tolerated and causes fewer gastrointestinal disturbances than the majority of its class.
Ibuprofen works by blocking the action of a substance in the body called cyclo-oxygenase (COX). Cyclo-oxygenase is involved in the production of various chemicals in the body, known as prostaglandins. Prostaglandins are produced in response to injury and certain diseases and conditions, and cause pain, swelling and inflammation. NSAIDs block the production of these prostaglandins and are therefore effective at reducing inflammation and pain. As a result it reduces fever by reducing the production of prostaglandins. It can be concluded that ibuprofen lowers the body temperature by reducing the prostaglandins in the brain.
It is known to cause wheezing in some asthmatics. In addition to this, it is also mild to moderate pain including rheumatic and muscular pain, sprains and strains, backache, nerve pain (neuralgia), migraine, headache, toothache, period pain. Other mild symptoms may include: Feverishness and symptoms of colds and flu.
COX-2 SELECTIVE INHIBITORS
Popular NSAIDS are unable to distinguish between the two types of COX enzymes, thus leading to therapeutic effects through inhibition of COX-2 and more severe effects such as gastrointestinal problems, ulcers and bleeding via inhibition of COX-1. Since, differences exist in the active sites of these enzymes, it has been possible to develop new anti-inflammatory drugs that can inhibit COX-2 rather than COX-1. These are the 'coxib' drugs. 'Coxib', COX-2 selective inhibitors, have been found to cause less gastro-intestinal side effects; however carry an increased risk of cardiovascular events that include strokes and heart attacks.
When prescribing COX-2 inhibitors care has to be taken about patients with conditions such as high blood pressure, high cholesterol, diabetes and smoking that are risk factors for heart disease. Additional care has to also be taken when C0X-2 drugs are prescribed to patients with no related heart risk, but are taking low dose aspirin, as evidence suggests that gastro intestinal safety advantage is reduced when both are taken together.
Three clinical agents selective for COX-2 are currently available for use in the UK: Celecoxib, Etoricoxib and Parecoxib. These are introduced to help in relief of pain and inflammation in osteoarthritis and rheumatoid arthritis.
Celecoxib and Etoricoxib
These are licensed for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and acute gout. Both the drugs achieve peak plasma concentration within one to three hours and are extensively metabolised in the liver, and have high plasma binding.
These may include fatigue, headache, dizziness, skin rashes, peripheral oedema that is caused by fluid retention.
Care has to be taken, as with COX-2 inhibitors, about the possibility of serious adverse cardiovascular events. Caution should be taken when prescribing the drugs to patients with connective tissue disorders.
It is a prodrug of valdecoxib. Parecoxib is licensed for the short term treatment of acute postoperative pain.
The process of enzymatic hydrolysis in the liver allows conversion of Parecoxib active Valdecoxib. Plasma protein binding is high. Valdecoxib, the active metabolite, is eliminated through hepatic metabolism.
Some of them may include hypotension, hypertension, peripheral oedema, pharyngitis (an inflammatory condition that affects the wall of the pharynx and the throat), respiratory insufficiency, postoperative anaemia, back pain, increased blood urea nitrogen and in rare circumstances vomiting. Some of the serious reactions may include Steven-Johnson syndrome and toxic epidermal necrolysis (disintegration of the dead tissue).
Commission of Human Medicines recommends that NSAIDS should be prescribed in the lowest effective dose possible and for the shortest period of time. However this is highly unlikely, as the conditions for which NSAIDS are needed are used, e.g. osteoarthritis, RA and ankylosing spondylitis need long term treatment.
NSAIDS suppress bone formation and have been used to prevent unwanted ossification following hip replacement. However, in the long term cause an increase in cartilage damage and also. The principal contra-indications of Ibuprofen include: Renal dysfunction and disorders of the GI tract. The risks of its long action include anti platelet therapy and anticoagulant.
Elderly and asthmatic patients may have contra-indications to: hypertension, heart failure, epilepsy, psychotic disturbances or Parkinson may be worsened (particularly indometacin). Other risks may include; High risk of bleeding, for example, liver failure (particularly dangerous with oesophageal varices ), thrombocytopenia, vitamin K or C deficiency, peptic ulceration, haemorrhagic stroke. Systemic complications may arise when large doses are used; as a result, inflammatory bowel disease may progress without recognition (particularly to enteric-coated NSAIDs), due to 'masking' of symptoms. Conversely, low doses may be prescribed in mild renal failure but NSAIDs (including topical applications) are contra-indicated in moderate/severe renal failure.
On the other hand, COX-2 inhibitors have been contra-indicated to the patients with:
- Cerebrovascular disease
- Moderate to severe heart failure
- Significant risk factors for cardiovascular events, such as diabetes mellitus, hyperlipidaemia, hypertension and smoking and peripheral artery disease.
Unfortunately, NSAIDs are also contra-indicated in severe heart failure. Hypertension may be worsened, particularly COX2 inhibitors. Cardiovascular and cerebrovascular disease: COX2 inhibitors are contra-indicated. Prostaglandins are of great importance in childbirth, use of it in pregnancy is associated with higher risks of bleeding, miscarriage, prolonged labour, intra-uterine growth retardation. Alongside, use in third trimester may affect foetal heart, lungs or kidneys. To overcome this, paracetamol may be advised as an alternative, but prolong use in late pregnancy may be linked to infant wheezing.
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