NSAIDs' three key types of effects

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Majority of NSAIDs have three key types of effects, those being: analgesic effect (lessens certain categories of pain), antipyretic effect (where increased temperatures are lowered) and anti-inflammatory effects (changes to the inflammatory reaction).

COX-1 and COX-2 are the two different types of cyclooxygenase enzymes. The arachidonate cyclooxygenases are inhibited by NSAIDs which hence results in the inhibition of thromboxanes and prostaglandins. COX-1 is found in many tissues in the body such as well as blood platelets and is a constitutive enzyme. One of the roles COX-1 has in the body is tissue homeostasis. Once COX-2 enzymes are triggered they are induced into inflammatory cells, and therefore prostanoid mediators of inflammation are required for production by COX-2. There is also a recently discovered COX enzyme, COX-3 which could be associated with fever.

The inhibition of COX-2 by NSAIDs is mainly the reason for their anti-inflammatory activity, and their inhibition of COX-1 results in the unwanted affects mainly those that interfere with the gastrointestinal tract.

ANALGESIC EFFECT:

The cause of pain from inflammation or damage to tissues is where NSAIDs come in handy as they decrease the synthesis of prostaglandins (those that sensitise nociceptors to inflammatory mediators) similar to the ones called bradykinin. Hence they are useful with conditions related to increased prostaglandin production. In some situations the need of opiods (which are combined with to reduce postoperative pain) can be depreciated by up to a third. This is known as the peripheral effect and there is another type of effect one which is not as a well-characterised action, which is central and may occur within the spinal cord. In the cord the release of prostaglandin is increased by the inflammatory lesions which assist the transmission in the dorsal horn to the relay neurons from the afferent pain fibres.

ANTIPYRETIC EFFECT:

The centre of the hypothalamus which is located in the brain regulates the temperature in the body and maintains the equilibrium of the production of heat and heat loss. When there is a disorder in this balance (of the hypothalamic thermostat) and the temperature of the body is increased, the body suffers from a fever. NSAIDs help to reverse this and return the body temperature to normal body temperature, the temperature-regulating mechanisms act once the normal set point is reached to lower the temperature. However, NSAIDs do not have any actions towards our normal body temperatures. In the hypothalamus, the production of prostaglandins is stopped by the antipyretic affect is carried out by NSAIDs. E-type prostaglandins in the hypothalamus which make the temperature set point higher are stimulated by pyrogen - IL-1. Pyrogen is released from macrophages by bacterial endotoxins in an inflammatory reaction. COX-2 may be related here as it may have an associated function because in the vascular endothelium located in the hypothalamus the COX-2 is induced by IL-1. This may not be the only type of antipyretic affect that NSAIDs have because there is various evidential information that intermediaries of fever are not only prostaglandins. The mechanism of other antipyretic effects are not factual as of yet.

ANTI-INFLAMMTORY EFFECTS:

Inflammatory reactions and allergic reactions such as hay fever are controlled by various intermediaries. Some intermediates i.e. histamine in allergic inflammation are made in reaction to particular stimuli, there is a lot of redundancy and every component related to the response can be made by many individual mechanisms. The parts of the immune and inflammatory response where prostaglandins (primarily derived from COX-2 enzymes) take part in an important function are reduced by NSAIDs. These involve: Oedema, pain and vasodilatation. NSAIDs do not have any major roles on the chronic disease nonetheless they restrain swelling, elevated blood flow and pain linked with inflammation.

Unwanted effects of NSAIDs:

Skin reactions such as rashes (common idiosyncratic effects) can results from the use of NSAIDs especially with sulindac and mefenamic acid. These differ from cases like urticarial, mild erythematous and photosensitivity reaction to more severe cases (which are rare) like the Steven-Johnson syndrome.

  • Adverse Renal Effects:
  • Gastrointestinal Disturbances:
  • Other unwanted effects:

ASPIRIN

Aspirin is the model opioid drug that reduces pain at mainly peripheral sites with few cortical interactions, and therefore there are fewer CNS effects. Aspirin is now one of the oldest known drugs able to reduce pain and fever, and is a weak organic acid. The effectiveness of NSAIDs is still compared to aspirin which remains the standard for comparison.

Aspirin has poor solubility in water (insoluble), but this solubility can be improved with the derivatives of the drug such as calcium or sodium salts, and it is an acid with a pKa of 3.5. When taken orally aspirin and other related salicylates (also have anti-inflammatory actions, and aspirin was originally derived from salicylate) are absorbed swiftly and most of this absorption happens within the small intestine. The stomach is a secondary site where drug absorption may take place and also gastric emptying time of the stomach. The pH of the stomach can determine how fast or slow the absorption of the drug takes place. Hence the absorption of the drug may change with food intake which adjusts the gastric emptying time and could also alter the pH of the stomach. The solubility of the drug can be increased and irritation to the stomach can be decreased by buffering of the drug and this is turn may increase the speed of absorption. In the stomach and the liver, aspirin is hydrolysed straight away by a number of esterases to salicylic acid and acetate. Then the salicylic acid is either conjugated to glycine to produce salicyluric acid, glucuronidated, converted to gentistic acid by oxidation or stays as free salicylic acid which is released into the kidney within the proximal tubule. The pharmacokinetics of aspirin combined with other drugs taken at the same time is effected by the face that salicylic acid if extremely plasma protein bound. The salicylates submissively diffuse to all tissues, together with fetal tissues, CNS and breast milk. However renal clearance relies on the urine pH, the greater the pH the better the drug clearance. In the case of overdose or toxicity alkalinisation is used for the clearance of these salicylates.

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS:

The pharmacological effects of aspirin and other related salicylates are produced by mainly inhibiting prostaglandin synthesis, and also to a small degree inhibition of thromboxanes which are concerned with platelet aggregation. In many types of cells the prostanoids are intermediaries of inflammatory responses. The difference of aspirin than that of NSAIDs is that aspirin permanently acetylates the induced and constitutive types of COX-1 and COX-2, which are needed in the synthesis of prostanoids from arachadonic acid. Most of the inflammatory responses are thought to be mediated by COX-2 as it is brought about during inflammation. COX-1 is permanently inactivated when it is acetylated by aspirin, whereas when COX-2 is acetylated it has the ability to produce 15-HETE. Overcoming the effects of aspirin requires the synthesis of new enzyme; this can take up to 11 days when considering platelets. Salicylic acid, which is a metabolite of aspirin, is a reversible inhibitor of COX. On other sites on COX-1 and COX-2 different NSAIDs also have reversible effects. Moreover aspirin impedes with the kinin-induced modulation related to the inflammatory response.

Aspirin (as well as other related salicylates) is used as the main treatment for muscle and joint pain, dysmenorrhea and mild to moderate pain i.e. those such as headaches.

Paracetamol (4-acetamidophenol) also known as acetaminophen is used for the treatment of fever and colds in both children and adults. It can be obtained as both prescription and as an over-the-counter medicine. Paracetamol has no real side-effects when taken at the stated doses and can be taken by anyone of any age, sex or condition. Paracetamol can be used by those whom are sensitive to aspirin and endured by those with peptic ulcers. The dose form is usually tablet for immediate consumption, although it is available in liquid formulation which might be ideal for young children. Similarly to aspirin, paracetamol also has analgesic and antipyretic effects for pain and fever relief. But increased dosages do not help with anti-inflammatory affects unlike aspirin and NSAIDs; hence they cannot be used for anti-inflammatory uses though they are still very good pain relievers. Symptoms for conditions such as influenza, common cold and sinusitis can be relieved by paracetamol when combined with decongestant ingredients to relieve nasal congestion, headaches, fever and general aches.

As we know already NSAIDs such as aspirin can cause gastrointestinal side effects due to their activity of blocking COX-1. However, paracetamol does not cause any unwanted gastrointestinal effects, as it does not act on COX-1 and COX-2; this also explains why they have an inability of anti-inflammatory action. The reason for this is unknown but recent research carried out has shown that there is also a COX-3 cyclooxygenase enzyme located in the spinal cord and the brain which is distinct to both the known enzymes COX-1 and COX-2 cyclooxygenase. Paracetamol selectively inhibits the COX-3 enzyme; which reduces fever and relieves pain but at the same time avoids any unwanted gastrointestinal side effects.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a category of medicines which are utilized to ease: inflammation, stiffness, mild to moderate pain and fever. Their anti-inflammatory action is equal to that of aspirin; they have antipyretic, analgesic and platelet-inhibitory effects

The difference to that of aspirin is that the effects on platelet aggregation are temporary by NSAIDs. All NSAIDs are not permitted for identical functions. A series of different medical conditions that cause pain are also treated using NSAIDs. They can be found in both generic and brand-name versions and are obtained via prescription or non-prescription strengths. Hormones called prostaglandins which are the cause of pain and inflammation are thought to be inhibited by NSAIDs. NSAIDs can be used alongside other medications used to treat sinus, flu and many common cold products. These can be used to help with sinus problems, fever and flu symptoms or aches and pains.

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