Repan (Acetaminophen)

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Repan is one brand name of the medicine also known by its generic name Acetaminophen. This page displays only reviews left by users of Repan. Click here to see all reviews left for all forms of Acetaminophen. You can also choose other review combinations.

More about Acetaminophen

What is/are Acetaminophen?

Acetaminophen (marketed as Orencia) is a fusion protein composed of the Fc region of the immunoglobulin IgG1 fused to the extracellular domain of CTLA-4. It is a molecule capable of binding with more avidity to CD80 (B7-1) than to CD86 (B7-2). Abatacept is a selective co-stimulation modulator as it inhibits the costimulation of T cells. It was developed by Bristol-Myers Squibb and is licensed in the United States for the treatment of rheumatoid arthritis in the case of inadequate response to anti-TNFα therapy.

Medical uses


Paracetamol is approved for reducing fever in people of all ages. The World Health Organization (WHO) recommends that paracetamol only be used to treat fever in children if their temperature is greater than 38.5 °C (101.3 °F). The efficacy of paracetamol by itself in children with fevers has been questioned and a meta-analysis showed that it is less effective than ibuprofen.


Paracetamol is used for the relief of pains associated with many parts of the body. It has analgesic properties comparable to those of aspirin, while its anti-inflammatory effects are weaker. It is better tolerated than aspirin in patients in whom excessive gastric acid secretion or prolongation of bleeding time may be a concern. Available without a prescription, it has in recent years increasingly become a common household drug.

Paracetamol can relieve pain in mild arthritis[citation needed] but has no effect on the underlying inflammation, redness, and swelling of the joint. It is as effective as the non-steroidal anti-inflammatory drug (NSAID) ibuprofen in relieving the pain of osteoarthritis of the knee.

Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics such as the NSAIDs aspirin and ibuprofen. But research studies analysis showed that ibuprofen and paracetamol have similar effects in the treatment of headache.

Regarding comparative efficacy, studies show conflicting results when compared to NSAIDs. A randomized controlled trial of chronic pain from osteoarthritis in adults found similar benefit from paracetamol and ibuprofen.

The efficacy of paracetamol when used in a combination form with weak opioids (such as codeine) has been questioned by recent data studies; the small amount of data available have made reaching a conclusion difficult. Combination drugs of paracetamol and strong opioids like morphine have been shown to reduce the amount of opioid used and improve analgesic effect as well as discouraging overuse of addictive opioids due to APAP's toxic effects, as it depletes glutathione and thus exacerbates disease in general.

A randomized controlled trial of acute musculoskeletal pain in children found that the standard over-the-counter dose of ibuprofen gives greater pain relief than the standard dose of paracetamol.

Psychological effects

Paracetamol acts on, and suppresses pain through, the central nervous system rather than the peripheral nervous system. Recent research suggests that it deadens the neural response that causes the pain of social rejection as well as neural responses related to physical pain.

Adverse effects

Paracetamol is metabolized by the liver and is hepatotoxic; side effects are multiplied when combined with alcoholic drinks, and very likely in chronic alcoholics or patients with liver damage. Prolonged daily use increases the risk of upper gastrointestinal complications such as stomach bleeding, and may cause kidney or liver damage. And chronic users of paracetamol may have a higher risk of developing blood cancer. However in recommended doses and for a limited course of treatment, the side effects of paracetamol are mild to non-existent.

In contrast to aspirin, paracetamol is not an antithrombotic, and thus may be used in patients where coagulation is a concern, and it does not cause gastric irritation. However, paracetamol does not help reduce inflammation, while aspirin does. Compared to ibuprofen—whose side effects may include diarrhea, vomiting and abdominal pain—paracetamol has fewer adverse gastrointestinal effects.

Until 2010, paracetamol was believed safe in pregnancy (as it does not affect the closure of the fetal ductus arteriosus as NSAIDs can). However, in a study published in October 2010 it has been linked to infertility in the adult life of the unborn. Unlike aspirin, it is safe for children, as paracetamol is not associated with a risk of Reye's syndrome in children with viral illnesses. In one study, paracetamol use for fever in the first year of life was associated with a moderate increase in the incidence of asthmatic symptoms at 6–7 years, and that paracetamol use, both in the first year of life and in children aged 6–7 years, was associated with a moderate increased incidence of rhinoconjunctivitis and eczema.

Mechanism of action

To date, the mechanism of action of paracetamol is not completely understood. The main mechanism proposed is the inhibition of cyclooxygenase (COX), and recent findings suggest that it is highly selective for COX-2. While it has analgesic and antipyretic properties comparable to those of aspirin or other NSAIDs, its peripheral anti-inflammatory activity is usually limited by several factors, one of which is the high level of peroxides present in inflammatory lesions. However, in some circumstances, even peripheral anti-inflammatory activity comparable to NSAIDs can be observed. An article[54] in Nature Communications from researchers in London, UK and Lund, Sweden in November 2011 has found a hint to the analgesic mechanism of paracetamol (acetaminophen), being that the metabolites of paracetamol e.g. NAPQI, act on TRPA1-receptors in the spinal cord to suppress the signal transduction from the superficial layers of the dorsal horn, to alleviate pain. This conclusion has been contested in a new hypothesis paper on how paracetamol might act. The author concedes that NAPQI is the active metabolite but that this reactive compound should react not only with the thiol in TRPA1 but also with any other suitably available nucleophile that it happens to encounter. It is suggested that thiol groups in cysteine proteases, e.g. the proteases that take part in the processing of procytokines, such as those generating IL-1β and IL-6, might be the targets giving rise to overall analgesic effects.

Because of its selectivity for COX-2 it does not significantly inhibit the production of the pro-clotting thromboxanes.

The COX family of enzymes are responsible for the metabolism of arachidonic acid to prostaglandin H2, an unstable molecule that is, in turn, converted to numerous other pro-inflammatory compounds. Classical anti-inflammatories such as the NSAIDs block this step. Only when appropriately oxidized is the COX enzyme highly active.

Paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming pro-inflammatory chemicals. This leads to a reduced amount of prostaglandin E2 in the CNS, thus lowering the hypothalamic set-point in the thermoregulatory centre.

Paracetamol also modulates the endogenous cannabinoid system. Paracetamol is metabolized to AM404, a compound with several actions; what is most important is that it inhibits the reuptake of the endogenous cannabinoid/vanilloid anandamide by neurons. Anandamide reuptake would result in lower synaptic levels and less activation of the main pain receptor (nociceptor) of the body, the TRPV1 (older name: vanilloid receptor). By inhibiting anandamide reuptake, levels in the synapse remain high and are able to desensitize the TRPV1 receptor much like capsaicin. Furthermore, AM404 inhibits sodium channels, as do the anesthetics lidocaine and procaine. Either of these actions by themselves has been shown to reduce pain, and are a possible mechanism for paracetamol. However, it has been demonstrated that, after blocking cannabinoid receptors with synthetic antagonists, paracetamol's analgesic effects are prevented, suggesting its pain-relieving action involves the endogenous cannabinoid system. Spinal TRPA1 receptors have also been demonstrated to mediate antinociceptive effects of paracetamol and 9-tetrahydrocannabinol in mice.

Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes and, because paracetamol's action is partially similar to aspirin's, much research has focused on whether paracetamol also inhibits COX. It is now clear that paracetamol acts via at least two pathways.

The exact mechanisms by which COX is inhibited in various circumstances are still a subject of discussion. Because of differences in the activity of paracetamol, aspirin, and other NSAIDs, it has been postulated that further COX variants may exist. One theory holds that paracetamol works by inhibiting the COX-3 isoform - a COX-1 splice variant - of the COX family of enzymes. When expressed in dogs, this enzyme shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol.[66] However, some research has suggested that, in humans and mice, the COX-3 enzyme is without inflammatory action and paracetamol's blockage of it is not significant in its functioning in humans. Another possibility is that paracetamol blocks cyclooxygenase (as in aspirin), but that, in an inflammatory environment where the concentration of peroxides is high, the high oxidation state of paracetamol prevents its actions. This idea would mean that paracetamol has no direct effect at the site of inflammation, but instead acts in the CNS where the environment is not oxidative, to reduce temperature, etc. The exact mechanism by which paracetamol is believed to affect COX-3 is disputed.

Paracetamol's increase of social behavior in mice (which corresponds to its reduction of social rejection response in humans) does not appear to be due to cannabinoid receptor type 1 activity. It may result from serotonin receptor agonism.


Paracetamol is part of the class of drugs known as "aniline analgesics"; it is the only such drug still in use today. It is not considered an NSAID because it does not exhibit significant anti-inflammatory activity (it is a weak COX inhibitor). This is despite the evidence that paracetamol and NSAIDs have some similar pharmacological activity.

Structure and reactivity

Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern. The amide group is acetamide (ethanamide). It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon, and the lone pair on the carbonyl oxygen are all conjugated. The presence of two activating groups also make the benzene ring highly reactive toward electrophilic aromatic substitution. As the substituents are ortho, para-directing and para with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces the basicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the phenoxide anion.



In the laboratory, paracetamol is easily prepared by nitrating phenol with sodium nitrate, separating the desired para- nitrophenol from the ortho- byproduct, and reducing the nitro group with sodium borohydride. The resultant 4-aminophenol is then acetylated with acetic anhydride. In this reaction, phenol is strongly activating, thus the reaction requires only mild conditions (cf. the nitration of benzene). The industrial process is analogous, but hydrogenation is used instead of the sodium borohydride reduction.

A simpler synthesis by Hoechst-Celanese involves direct acylation of phenol with acetic anhydride catalyzed by HF, conversion of the ketone to a ketoxime with hydroxylamine, followed by the acid-catalyzed Beckmann rearrangement to give the amide.
Demand for paracetamol in the United States was estimated at 30–35 thousand tonnes per year in 1997, equal to the demand from the rest of the world.


Paracetamol is metabolised primarily in the liver, into toxic and non-toxic products. Three metabolic pathways are notable:

  • Glucuronidation is believed to account for 40% to two-thirds of the metabolism of paracetamol.
  • Sulfation (sulfate conjugation) may account for 20–40%.
  • N-hydroxylation and rearrangement, then GSH conjugation, accounts for less than 15%. The hepatic cytochrome P450 enzyme system metabolizes paracetamol, forming a minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzo-quinone imine)(also known as N-acetylimidoquinone). NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione.

All three pathways yield final products that are inactive, non-toxic, and eventually excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is primarily responsible for the toxic effects of paracetamol; this constitutes an example of toxication.

Production of NAPQI is due primarily to two isoenzymes of cytochrome P450: CYP2E1 and CYP1A2. The P450 gene is highly polymorphic, however, and individual differences in paracetamol toxicity are believed due to a third isoenzyme, CYP2D6. Genetic polymorphisms in CYP2D6 may contribute to significantly different rates of production of NAPQI. Furthermore, individuals can be classified as "extensive", "ultrarapid", "intermediate" and "poor" metabolizers (producers of NAPQI), depending on their levels of CYP2D6 expression. Although CYP2D6 metabolises paracetamol into NAPQI to a lesser extent than other P450 enzymes, its activity may contribute to paracetamol toxicity in extensive and ultrarapid metabolisers, and when paracetamol is taken at very large doses. At usual doses, NAPQI is quickly detoxified by conjugation with glutathione. Following overdose, and possibly also in extensive and ultrarapid metabolizers, this detoxification pathway becomes saturated, and, as a consequence, NAPQI accumulates causing liver and renal toxicity.


4-Aminophenol may be obtained by the amide hydrolysis of paracetamol. 4-Aminophenol prepared this way, and related to the commercially available Metol, has been used as a developer in photography by hobbyists. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, 4-aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form an indophenol dye under oxidization by air.

This article uses material from the Wikipedia article Acetaminophen , which is released under the Creative Commons Attribution-Share-Alike License 3.0.

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