Non-steroidal anti-inflammatory drugs
The non-steroidal anti-inflammatory drugs (NSAIDs) are used most commonly, compare with all other drugs. They are mainly used to treat postoperative, dental, and menstrual pain and pain of headache and migraine. They also used to treat symptoms of pain and swelling in chronic joints disease such as rheumatoid arthritis, and in more inflammatory conditions such as sport injuries, fractures, sprains and other soft tissue injuries. Most of the NSAIDs are available over the counter without prescription and most commonly used to treat miner headache and pains. They are also available in many dosage forms such as tablets, pill, capsule,drinkorsyrup injections and gels. There are a lot of unwanted side effects related to NSAIDs, most commonly in young children and old people. However the new remedies have fewer unpleasant effects.
One of the major beneficial effect of NSAIDs is antipyretic effect; these drugs effectivly reduce high temperature cause by disease i.e. fever. Other useful effects include anti inflammatory effect; they cause change in inflammatory reaction. They also have analgesic effect which means they reduce certain types of inflammatory pain caused by disease.
On the other hand NSAIDs have certain unwanted mechanical based side effects. They are one of the main cause of extended bleeding as they inhibit the platelets action in blood, they are also involve in stomach disorders which include Gastric irritations and it could lead to simple certain miner problems in stomach to ulcer formation. They also cause renal blood flow in the compromised kidney.
Signaling pathways and Mechanisms of action
Cycloocygenase (COX) is enzyme which involve in synthesis of important biological mediators calledprostanoids, such as prostaglandins, prostacyclinand thromboxane. COX are inhibited by NSAIDs such as aspirin and ibuprofen to provide relief from symptoms of inflammation and pain. COX are used to convert arachidonic acidto prostaglandin.
COX enzyme have two active sites on their structure; heam with peroxide activity it is mainly responsible for reduction of PGG2to PGH2 and the other site is cyclooxygenase site, this is the site where arachidonic acid is converted into the hydroperoxy endoperoxide prostaglandin G2(PGG2).
There are three main type of COX isoenzyyme which include COX-1, COX-2 and COX-3. COX-1 and COX-3 are quite similar in structure.
Different parts of the body contain different amount of COX-1 and COX-2 enzymes. They have similar function but different in terms of side effects, where COX-1 is the most common enzyme found in all mammalian cells.
COX-1 and COX-2 are closely related in terms of molecular weight, amino acid sequence and catalytic sites. However one major difference is the substitution ofisoleucineat position 523 inCOX-1withvalineinCOX-2. The smaller residue in COX-2 allows access to a hydrophobic side pocket in enzyme. Therefore active ingredients from drug bind to this site and act as selective inhibitors.
The major COX inhibitors are the non-steroidal anti-inflammatory drugs(NSAIDs). All most all the NSAIDs have different actions but they all depend on basic action of drug, which involves inhibiting the COX enzyme and therefore inhibition of production of enzyme prostaglandins. The two main type of COX enzyme are COX-1 and COX-2. These two enzymes are very similar in their function but they have some certain differences in role and expression.
COX-1 is one of the most common enzymes expressed in almost all the tissues and blood platelets. It is mainly involve in keeping the internal environment of tissue constant and production prostaglandin. There are certain other function associated with it, which involves gastric cytoprotection, platelets aggregation, renal blood flow auto regulation and the initiation of parturition.
On the other hand COX-2 enzymes are involved in inflammatory cells, this is where they synthesised and activated. This is why COX-2 enzymes are main source of production of prostanoid mediator of significant exceptions. There is a large amount of COX-2 could be found in central nervous system (CNS) and some other tissues.
All the NSAIDs perform their function by inhibiting the COX enzymes but each NSAID enzyme has its own different pathway of action. The basic Anti-inflammatory action of NSAIDs is caused by inhibition of COX-2 enzyme and the unwanted effects mainly those affecting the gastrointestinal tract are mostly caused by action of their inhibition of COX-1. The compounds which only inhibit the COX-2 enzyme are now clinically available but due to increase in cardiovascular risk the treatment of inflammatory conditions have received a setback.
Mostly non-steroidal anti-inflammatory drugs are weakly acidic, they have a pKa of 3-5. This is one of the main reasons that they absorb well in thestomach wallsand intestinal mucosa. They have high tendency to form bonds with proteins in plasma therefore their volume of distribution is similar to plasma volume. NSAIDs are mostly metabolised in liver by oxidation and conjunction to inactive metabolites which are then excreted from urine, even some drugs excreted inbile. Metabolism could be abnormal in some disease states and cause accumulation with normal dosage.
Some of the NSAIDs have very short half- life from two to three hours i.e. Ibuprofen where as other may have very long half-life up to 60 days
Aspirin which is also called acetylsalicylic acid is one of the most commonly used drugs. Aspirin has very good anti-inflammatory, antipyretic and antiplatelet properties. Aspirin is batter then other NSAIDs in its action as it acts as a non competitive inhibitor for enzymes COX where as other NSAIDs act as competitive inhibitors. Aspirin was first extracted from willow bark in the form of salicylic acid, which was later altered to form aspirin. Salicylic acid has same functions as aspirin but it doesn't form platelets in blood when needed. Today aspirin is available in different dosage forms i-e tablets, syrups and dissolve able powders.
Aspirin is weakly acidic therefore it could take directly from mouth and easily absorbed in stomach walls and have systematic effects. If aspirin is taken in, when stomach is full it will mix up with stomach content and absorbed more rapidly. However if aspirin is taken with empty stomach it might cause gastric erosions. In small intestine aspirin has lipophobic properties but due to large surface area of ileum, it absorb readily this is why aspirin absorption is relatively fast in intestine.
Aspirin is one of the main drugs used for treatment of migraine, it is equally effective as other drugs such as paracitamol and ibuprofen but it is associated with its own gastrointestinal side effects. It is said that aspirin and paracetamol are used to treat all sorts of headaches but aspirin have it certain unpleasant side effect which include, more stomach discomfort, nervousness and dizziness.
Normally aspirin work well against all miner body pains. However aspirin don't have any major effect in treating symptoms such as most muscle cramps, bloating,gastric distensionand acute skin irritation. Aspirin can also be taken with caffeine to boost its effect against pain. Certain types of pains such as post surgical pain aspirin are less effective therefore ibuprofen is a more proffered drug instead.
Prevention of heart attacks and strokes
Aspirin is used in two ways to stop prophylactics of cardiovascular events. First of all it prevent heart attack in population with undiagnosed heart problem, secondly it prevent people with known heat disease.
Small dose of aspirin is recommended to prevent both male and female from heart attack, it reduces the chance of a heart attack andischemic strokeby about a fifth. Aspirin also increase the risk of hemorrhagic strokeand other majorbleedsby about two-fold, although the chance of these events to occur is small therefore aspirin have over all positive effect. For people who don't have cardiovascular problems, aspirin might be not as use full as the overall reduction in heart problem is low compare to its side effects including hemorrhagic strokes and gastrointestinal bleeding.
Aspirin should be taken after Coronary artery bypasses and stents replacement; coronary attires take blood from heart to muscles under high pressure. Recommended dose is after 1 to 6 month.
Aspirin is also advised to patients with mildcarotid artery stenosis and after acarotid endarterectomyor after placement of a carotid arterystent. Thecarotid arteries are the major arteries which take blood from heart to the brain.
Aspirin is used to prevent us from fever, pain and high temperature due to common cold from hundreds of years. However latest research on mechanism of drugs and effects show 1 g of aspirin reduce the body temperature of an adult from 39.0C to 37.6C after 3 hours. The relief starts after 30 minutes and the temperature stays the under 37.8C for 6 hours. Aspirin also provide relief from headache, itchiness discomfort and sore throat.
Common adverse effects
Although aspirin is used on such a large scale worldwide but it has some unwanted side effect, some of the complications could be serious; Aspirin is fairly safe drug if bleeding or ulcers don't occur. If aspirin is used to treat long term miner illnesses and pains it cause renal damage. Aspirin can also cause allergic reaction depending on individuals this is due to inhibiting of prostaglandin and arachidonic acid. If several grams of aspirin are taken a day diachronic aspirin poisoning could occur.
Mechanism of action
Aspirin belong to a group of drugs called salicylates, they all have analgesic anti-inflammatory properties. Aspirin have the most antiplatelets properties in the whole group. This is because they have acetyl group present in them. This acetyl group present in aspirin react with COX enzymes, which are needed for the synthesis of thromboxane. Aspirin is therefore a non comparative inhibitor for this enzyme. This makes the enzyme completely inactive.
Aspirin inactivate the cyclooxygenase(COX) enzyme permanently and reduce the production of prostaglandins and thromboxanes. COX enzymes are the main source for production of prostaglandin and thromboxane. Aspirin acts as an acetylating agent and anacetylgroup is covalently attached to the active site of the COX enzyme. This differentiates between aspirin and other NSAIDs which are reversible inhibitors.
Using low dosage of aspirin blocks the formation of thromboxane in platelets permanently and also produces an inhibitory effect onplatelet aggregation. The property of anticoagulant makes aspirin useful for reducing the chance of heart attack. Prostaglandins are hormones which are produced by body and have different effects within the body which include the transmission of pain information to the brain, modulation of thehypothalamicthermostat, and inflammation. Thromboxanes are the main cause for aggregation ofplateletsthat formblood clots. Mostly heart attack is caused blood clots and small dosage of aspirin is very effective in prevention of heart attack. The main side effect is that aspirin reduce the ability of blood to clot and therefore excessive bleeding could be occurring as a result of use of aspirin.
COX-1 and COX-2 inhibition
The two type of COX enzymes both effect by aspirin, COX-1 is permanently inhibited by aspirin and COX-2 enzymatic activity is also modifies by aspirin. COX-2 produces prostanoids which are pro-inflammatory therefore modified COX-2 produces lipoxins, which are mostly anti-inflammatory. New NSAIDs drugs inhibit only COX-2 selectively and reduce the incidence of gastrointestinal side-effects.
The part of brain is called hypothalamus, which is responsible for temperature regulation within the body. It controls the total amount of heat loss and heat production. Fever is caused by change in hypothalamus which in result rise the body temperature. Aspirin play key role in rearranging this thermostat and therefore bringing the body temperature to normal set point. However normal body temperature remains unaffected by the aspirin.
Antipyretic effect is caused by inhibition of prostaglandin within hypothalamus by aspirin. Bacteria release endotoxis which stimulate the release of prostaglandin. They cause in rising of body temperature from normal. There are some evidence that prostaglandin is not the only cause of rise in body temperature therefore aspirin also have some unknown key-role on antipyretic effect mechanisms as yet unknown
Aspirin is very effective against most of the body pain caused by inflammation or due to damage in body tissue. Aspirin work in two major areas which include peripherally, which mean reduce the production of prostaglandin which stimulate nociceptors to inflammatory mediators such as bradykinin and they are therefore effective in treatment of arthritis, bursitis, pain of muscular and vascular organs, toothache, dysmenorrhoea, the pain of postpartum states and the pain of cancer metastases in bone, they all linked with increase in synthesis of prostaglandin. Whereas opioids, decrease the postoperative pain, and reduce requirement of opioids by one third. Their effect on treatment of head ache could be linked to abrogation of vasodilator effect of prostaglandins on the cerebral vasculature.
Other then affects on brain they also have effects on spinal cold. Inflammation release prostaglandin in spinal cord, which cause facilitated transmission from afferent pain fibres to relay neurons in the dorsal horn.
Inflammatory and allergic reactions are caused by many mediators. Some of them are caused by response of a certain stimuli i-e call accumulation; the response for this is vasodilatation it could be caused by different mechanisms.
Vasodilatation, oedema and pain
Aspirin increases the blood flow associated with inflammation and therefore decrease the pain it don't have any direct effect on actual cause of disease. However aspirin don't have any direct effect on other aspects of inflammation, such as leucocyte migration, lysosomal enzyme release and toxic oxygen production which cause tissue damage in inflammatory conditions such as rheumatoid arthritis, vasculitis and nephritis.
Paracetamol do not have any direct effect on anti-inflammation and production of platelet. But paracetamol is useful analgesic in febrile illnesses such as influenza due to its antipyretic property.
Paracetamol don't interrupt with stomach activity like other NSAIDs because it don't inhibit prostaglandin in stomach because of their acid properties which inhibits prostaglandin and produce excess hydrochloric acid. Paracetamol should be taken while stomach is empty as it will increase the rate of absorption because it is not associated with Reye's syndrome. It could be used in children with viral infections.
Mechanism of action
Unlike other NSAIDs paracetamol works by reduce the synthesis of COX-3 enzymes. The major areas where his enzyme could be found are brain and spinal cord and are selectively inhibited by paracetamol. Paracetamol don't have any anti-inflammatory action and gastric side effects because it doesn't have any effect on COX-1 and COX-2 enzymes. This is why patacetamol only have antipyretic effects and don't have other peripheral adverse effects associated with the NSAIDs.
Common ADVERSE EFFECTS
Like all drugs paracetamol also have many adverse effects if use in excess. One of the major effects is liver failure. Alcoholic people are at greaster risk associated with acess amount of paracitamol as alcohol molecule increases the rate of conversion of paracetamol to its toxic metabolite.
Paracetamol reduces fever effectivly but it doesn't have any useful effect on actual cause of disease don't prevent febrile convulsions. In fact a febrile response shows the body's immune system is working to defeat micro-organisms.
Ibuprofen (originally marketed as brufen ) is also one of the NSAIDs drug, like all other NSAIDs it is also used to treat symptoms of ofarthritis, primarydysmenorrhoea,fever, and as ananalgesic, especially where there is an inflammatorycomponent. Ibuprofen however has anti-platelet effects but the effect is short term compare to other NSAIDs such as aspirin. It is one of the major medicine in essential drug list.
Mechanism of action
Ibufrofen like all other NSAIDs inhibits COX enzymes (which convert arachidonic acids to prostaglandins) and thromboxane (which propgate bloof clot in blood)
Ibrufon mainly inhibits two COX enzymes COX-1 and COX-2 therefore it is a non-selective COX. Most NSAIDs work by inhibiting COX enzyme to have useful effects such as Theanalgesic, antipyretic, and anti-inflammatory activity however the unwanted side effect are mainly caused by inhibition of COX-1 which involve onplatelet aggregation and the gastrointestinal tract. The roles of individual COX however still unknow. Different compounds cause different degrees of analgesia and gastric damage
Among all the NSAIDs ibuprofen has least gastrointestinaladverse drug reactions. This only applies to lower dose of ibuprofen. The main gerna adverse effects are nausea,dyspepsia, gastrointestinal ulceration/bleeding, raisedliver enzymes,diarrhoea,epistaxis,headache,dizziness,priapism, rash, salt and fluid retention and hypertension. Adverse effects include: oesophageal ulceration,heart failure,hyperkalaemia,renal impairment, confusion, andbronchospasm
Like all other drugs NSAIDs also have some adverse conditions or factors that increases therisksinvolved.
Aspirin have some certain contradictions which involve its effect on the stomach lining; people with kidney disease, peptic ulcers, milddiabetes, gout or gastritis are highly at risk from extended use of aspirin. If aspirin is used with alcohol it has high risk ofstomach bleeding. Aspirin is not suitable for children under the age of 12 as there is chance of Reye's syndrome. Aspirin should also not be used during Dengue Fever as it may cause increase in bleeding. Continuous use of aspirin could also cause risk of gastrointestinal bleeding. There are also risks involved in contamination of aspirin with other NSAIDs using aspirin with clopidogrel or warfarin also increases the risk of upper GI bleeding.
Aspirin's integration with other drugs i.e. acetazolamide and ammonium chloride increase the intoxicating effect of salicyclates, and alcolohol it also play major part in gastrointestinal bleeding involved in these types of drugs.