Acetaminophen Mechanism of action

Paracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of prostaglandins (PGs). However, the in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 (COX-2) inhibitors.


Paracetamol also decreases PG concentrations in vivo, but, unlike the selective COX-2 inhibitors, paracetamol does not suppress the inflammation of rheumatoid arthritis. It does, however, decrease swelling after oral surgery in humans and suppresses inflammation in rats and mice.

Paracetamol is a weak inhibitor of PG synthesis of COX-1 and COX-2 in broken cell systems, but, by contrast, therapeutic concentrations of paracetamol inhibit PG synthesis in intact cells in vitro when the levels of the substrate arachidonic acid are low (less than about 5 mumol/L). When the levels of arachidonic acid are low, PGs are synthesized largely by COX-2 in cells that contain both COX-1 and COX-2.

Thus, the apparent selectivity of paracetamol may be due to inhibition of COX-2-dependent pathways that are proceeding at low rates. This hypothesis is consistent with the similar pharmacological effects of paracetamol and the selective COX-2 inhibitors. COX-3, a splice variant of COX-1, has been suggested to be the site of action of paracetamol, but genomic and kinetic analysis indicates that this selective interaction is unlikely to be clinically relevant.

There is considerable evidence that the analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but its primary site of action may still be inhibition of PG synthesis. The action of paracetamol at a molecular level is unclear but could be related to the production of reactive metabolites by the peroxidase function of COX-2, which could deplete glutathione, a cofactor of enzymes such as PGE synthase.

Acetaminophen is thought to act primarily in the CNS, increasing the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin (PG) synthesis. Unlike NSAIDs, acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, thus, has no peripheral anti-inflammatory affects.

While aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme’s active site, studies have found that acetaminophen indirectly blocks COX, and that this blockade is ineffective in the presence of peroxides. This might explain why acetaminophen is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides. Studies also report data suggesting that acetaminophen selectively blocks a variant of the COX enzyme that is different from the known variants COX-1 and COX-2.

This enzyme is now referred to as COX-3. Its exact mechanism of action is still poorly understood, but future research may provide further insight into how it works. The antipyretic properties of acetaminophen are likely due to direct effects on the heat-regulating centres of the hypothalamus resulting in peripheral vasodilation, sweating and hence heat dissipation.

NSAIDs slow healing of Musculoskeletal Injuries

OTP pain medications are quite common in our day to day lives. Very few individuals think twice before they pop in a pill to get rid of strained muscle or pain due to headache. Many people are on medications while they recover from ligament tendon, severe muscle or bone injury. In such cases both NSAIDs and OTP are prescribed. These medications are accepted commonly to relieve inflammation and musculoskeletal injuries, for example naproxen, ibuprofen and aspirin.

People are now creating awareness about risk associated with prolonged use of NSAIDs, but dangers related to use for short-term still needs attention. NSAIDs though prove to be effective in reducing inflammation and relieving pain, but this action can also affect the process of healing a lot of injuries.

Inflammation and action of NSAID

Inflammation belongs to our immune system’s response to any injury. When our immune system detects a threat or an injury, it moves white blood cells and inflammatory fluids to the part to

  1. Separate the threat by obstructing the area from the rest of our body.
  2. Promotes tissue generation and healing

Obstruction of healing

When there is reduction of prostaglandins in our body it shows other effects apart from reducing the inflammation. These substances are helpful in bone reformation. This simply means that taking NSAIDs in order to relieve pain caused due to a bone fracture prominently delay the process of healing and result in failed fusion or bone setting.

NSAIDs have also affected the healing process of tendons, ligaments and soft tissues. Tendons connect muscles to our bones and ligament connects our bones together. These connective tissues get less blood supply and results in slow healing in case of ligament injuries and tendon. Fresh blood is important to deliver the required healing materials to the tissues that are injured and promote re-growth.

If you have normal muscle pain, NSAIDs can be effective in healing which lasts for say two to three days. In case of injuries that like bone injuries, or injuries related to tendons and ligaments, NSAIDs should not be taken for treating these injuries as the prolonged treatment involved can cause harm and slow healing process.

Remember you should not take NSAIDs if you have allergies as allergic reaction caused can be mild initially but it can also lead to severe conditions like hives, swollen throat, lips and tongue or asthma attacks. Also if you have a history of pre-existing condition of heart it can lead to heart problems. NSAIDs can also cause heart stroke or heart attack, high blood pressure and these effects are common in people taking these drugs for long term. If you have liver disease you shouldn’t take NSAIDs as they are processed through liver and if you’re liver functions aren’t normal you should avoid taking it.

NSAIDs can also affect the function of your kidney. The drugs prevent the kidney from flushing out the toxins out of the body. They are also not safe for pregnant women so pregnant women need to avoid taking them.

The potential risks associated with pain medicines used during pregnancy

Severe and persistent pain that is not effectively treated during pregnancy can result in depression, anxiety, and high blood pressure in the mother.  Medicines including nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and acetaminophen can help treat severe and persistent pain.   However, it is important to carefully weigh the benefits and risks of using prescription and OTC pain medicines during pregnancy.

The published studies reported on the potential risks associated with the following three types of pain medicines used during pregnancy :

  • Prescription NSAIDs and the risk of miscarriage in the first half of pregnancy. Examples of prescription NSAIDs include ibuprofen, naproxen, diclofenac, and celecoxib.
  • Opioids, which are available only by prescription, and the risk of birth defects of the brain, spine, or spinal cord in babies born to women who took these products during the first trimester of pregnancy.  Examples of opioids include oxycodone, hydrocodone, hydromorphone, morphine, and codeine.
  • Acetaminophen in both OTC and prescription products and the risk of attention deficit hyperactivity disorder (ADHD) in children born to women who took this medicine at any time during pregnancy.  Acetaminophen is a common pain reducer and fever reducer found in hundreds of medicines including those used for colds, flu, allergies, and sleep.

Pregnant women should always consult with their health care professional before taking any prescription or OTC medicine.  Women taking pain medicines who are considering becoming pregnant should also consult with their health care professionals to discuss the risks and benefits of pain medicine use.  Health care professionals should continue to follow the recommendations in the drug labels when prescribing pain medicines to pregnant patients.

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