Know your Medicine: PARACETAMOL

Paracetamol is a well-known over-the-counter medicine commonly used to relieve pain and bring down a fever. It is considered by The World Health Organization to be an essential medicine in a basic health system.

Paracetamol and acetaminophen are two official names of the same chemical compound N-(4- hydroxyphenyl) ethanamide having molecular formula C8H9NO2. 

Harmon Northrop Morse

Paracetamol was first synthesized by Harmon Northrop Morse, an American chemist in 1878. Two young doctors Arnold Chan and Paul Heppa at the University of Strasbourg, France, were studying how naphthalene affected intestinal parasites (worms), but they received acetanilide by mistake. To their surprise, they found that although acetanilide did not have much impact on intestinal parasites, it had antipyretic (fever-reducing) and analgesic (pain-relieving) properties. They quickly published their research and acetanilide was introduced into medical practice in 1886 under the name of antifebrine. 

Soon they observed that although the production cost of this drug was very low, acetanilide could not be used as an antipyretic agent due to its high toxicity. This resulted in a great deal of research on less toxic derivatives of acetanilide. Finally, after long research, its acetyl derivative, which was already synthesized by Morse, appeared to be the most satisfying compound. 

After its first synthesis in 1878, paracetamol became available to the general public with a doctor’s prescription in 1953. It was not until 1959 that paracetamol became available without a prescription. Today, paracetamol is a well-known medicine used for pain and fever. 

Paracetamol is most commonly used as an analgesic and is recommended as the first-line therapy to relieve pain by the World Health Organization (WHO). It is also used for its antipyretic effects, helping to reduce fever. 

Paracetamol provides relief from several common medical conditions such as headaches, muscle aches and pains, toothaches, arthritis, and fever. Paracetamol is often used combined with other drugs in more than 600 over-the-counter (OTC) allergy medications, cold medications, sleep medications, pain relievers, and other products. 

Because of its low risk of causing paracetamol can allergic reactions, be administered in patients who are intolerant to salicylates and those with allergic tendencies, including those with bronchial asthma. However, special guidelines need to be followed when administering it to children.

Mode of action

Animal and clinical studies have determined that paracetamol has both antipyretic and analgesic effects. It probably works by reducing the intensity of pain signals to the brain. It may also prevent the release of substances called prostaglandins that increase pain and body temperature. In the human brain, the hypothalamus works like a thermostat and it controls body temperature. 

During fever, a protein called pyrogen is generated. This increases the synthesis of compounds called prostaglandins in the hypothalamus, raising its temperature set point. Paracetamol acts as an antipyretic and inhibits the synthesis of prostaglandin. It reduces fever by promoting heat loss through sweating and cutaneous vasodilation and thus helps to lower the body temperature.

Precautions

Paracetamol has few side effects when taken at recommended doses. However, it is better to consult the doctor before taking paracetamol if you have liver or kidney problems or if you are taking other medicines because paracetamol may interfere with some of them. It is advisable not to take paracetamol if you are allergic to it. 

Paracetamol and liver failure 

Paracetamol is one of the most commonly used medicines for its analgesic and antipyretic properties. It is safe and effective at recommended doses, whereas overdose may lead to acute liver failure. In fact, paracetamol-induced liver damage has been observed in many countries. Attempts have been made by various researchers to understand the mechanisms of its toxicity. 

Generally, paracetamol-induced oxidative stress and mitochondrial dysfunction play a key role in this. The United States Food and Drug Administration recommends N-acetyl cysteine, a well-known antioxidant, as the only therapeutic option for patients affected by paracetamol over-dose; however, this treatment has its limitations including adverse effects and narrow therapeutic range. In the early stages, if the patients are not cared for properly, liver transplantation is the only option for their survival. 

Hence, the development of new drugs that are superior to N-acetyl cysteine, in terms of effectiveness and therapeutic time frame, is the need of the day. Recently, there have been intensive researches demonstrating the protective effects of natural products against paracetamol-induced hepatotoxicity, throwing up several future drug candidates. 

It has been recognized that paracetamol-induced liver toxicity consists of multi-stages and multi-signaling pathways, including metabolic activities, oxidative stress, endoplasmic reticulum (ER) stress, autophagy, sterile inflammation, microcirculatory dysfunction, and compensatory liver repair and regeneration. 

Many genes or molecules have been identified to play important roles in the regulation of paracetamol hepatotoxicity, so they are suggested to be potential targets for therapeutic intervention against paracetamol-induced liver damage.

When administered at therapeutic doses, most of the paracetamol is metabolized by phase II conjugating enzymes, mainly UDP-glucuronosyl transferase (UGT) and sulfotransferase (SULT), converting it to non-toxic compounds which are then excreted with the urine. Only a very small portion is excreted unchanged in the urine. The remaining paracetamol, approximately 5–9%, is metabolized by the cytochrome P450 enzymes (CYPs), mainly CYP 2E1 into the highly reactive intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQI).

Paracetamol and kidney failure

Paracetamol-induced liver necrosis has been studied extensively, but the manifestations of paracetamol toxicity outside the liver are currently not studied well in the available literature and it occurs in approximately 1-2% of patients with paracetamol overdose. 

Paracetamol-induced kidney failure studies have revealed that paracetamol is mostly metabolized through pro-cesses known as glucuronidation and sulfation whereas a lesser portion of the drug is metabolized through oxidation by the P-450 enzyme system. Metabolites are primarily generated in the liver and are excreted through the kidney. At therapeutic doses, N-acetyl-p-benzoquinone imine (NAPQI) that is generated from oxidized paracetamol is reduced to mercapturic acid by glutathione. 

Overdose of paracetamol depletes both glutathione and sulfate, then the metabolic pathway slides to oxidation. This situation resulted in lipid peroxidation that causes cell damage and apoptosis. Oxidation of paracetamol by the cytochrome P-450 system that may result in tubular damage and potentisation of the process by the depletion of glutathione in the kidney is also mentioned. 

Apoptosis induced by paracetamol has been shown in animal studies. In another study, it has been shown that paracetamol increases reactive oxygen radicals such as nitric oxide and this also contributes to cell damage.

FACTS:

• Paracetamol provides relief from several common medical conditions such as headaches, muscle aches and pains, toothaches, arthritis, and fever. Paracetamol is often used combined with other drugs in more than 600 over-the-counter (OTC) allergy medications, cold medications, sleep medications, pain relievers, and other products.

• Paracetamol has few side effects when taken at recommended doses. However, it is better to consult the doctor before taking paracetamol if you have liver or kidney problems or if you are taking other medicines because paracetamol may interfere with some of them. It is advisable not to take paracetamol if you are allergic to it.