Paracetamol: Drug Stories Part-III

 

Discovery of Acetaminophen

Acetamiophen is an analgesic and antipyretic agent with no anti-inflammatory action. Discovery of acetaminophen, more commonly known as paracetamol makes an interesting story. Discovery of paracetamol can be said to be a culmination of Serendipity, scientific acumen and diligence.

            

      
                                                             Photo by James Yarema on Unsplash

 

Industrial revolution brought a huge surge in commercial synthesis of many compounds, especially the dyes. There being a limited knowledge about biology, and a booming chemical industry led to testing of numerous compounds for various activities. The choice of activity to be studied was based more on expectations rather than rationale.

Under these circumstances, Arnold Cahn and Paul Hepp, sometime around 1886 at the University of Strasbourg had been involved in testing a variety of chemicals (mostly dyes and products from coal tar processing) against intestinal worms. One of these was naphthalene. Experiencing little success with other compounds, they however noted that a patient having a number of problems besides worm infestation, when administered naphthalene displayed a surprising yet unreported antipyretic (lowering of body temperature) effect. On further investigation, it was however revealed that the pharmacy had supplied their patient with acetanilide in place of naphthalene!

Acetanilide is a solid with a near-identical crystalline appearance to naphthalene. This chance discovery was duly published by Cahn and Hepp in 1886. The following year acetanilide was manufactured and marketed as Antifebrin. This antipyretic was effective and remarkably cheap too. Its use continued in a few over-the-counter preparations until 1971, when it came to light that patients using antifebrin were turning blue!  Their cyanosis was attributed to methemoglobinemia (a form of cyanosis caused by oxidation of the Fe(II) in haemoglobin to Fe(III), decreasing the  oxygen carrying capacity of iron) resulting from aniline, a metabolite of acetanilide.

It was soon replaced by a molecule called phenacetin.

As mentioned earlier, chemical industry was booming and the manufacturers were keen to find medicinal uses for their chemicals so that the business could become more lucrative. Thus, in one such attempt, a challenge was put forth by dyestuffs manufacturer Friedrich Bayer & Co to come up with an exploitable use for 4-nitrophenol, a side product available in vast amounts from its synthesis of the blue dye Benzazurin G that was being manufactured in their facility.

Oscar Hinsberg reported the synthesis of a compound which possessed all the advantages of antipyrin (a popular drug at that time) and antifebrin and (apparently) none of their disadvantages. A great chemist, he converted 4-nitrophenol in three steps, that is, reduction of -NO₂ to -NH₂; ethylation of the OH group; and finally acylation of the NH₂ group to give a well-tolerated antipyretic and analgesic named phenacetin.

This new product, phenacetin, enjoyed much popularity for almost a century as an ‘over-the-counter’ remedy often combined in tablets with caffeine and aspirin (APC).

APC was a very commonly used combination for headaches and hangovers. However, in the 1960s a number of studies suggested that phenacetin might be causing renal failure and renal tumours in some heavy users. In 1980 phenacetin was banned in the UK. A few years later it was banned in India too.    

Since it was a common practice to synthesise several analogues of an active molecule in order to find a better alternative, a number of analogues of phenacetin were prepared and one such derivative N-(4-hydroxyphenyl)ethanamide (later named paracetamol) was discovered and evaluated in 1893.

Germany's leading physiologist, Joseph von Mering was entrusted with the clinical trials of the drug by Bayer. Von Mering was unhappy with the results of his clinical trials because, while it was an effective analgesic and antipyretic, in some cases its use was associated with the development of methaemoglobinaemia (the kind observed with antifibrin). These observations made Bayer abandon paracetamol as a promising analgesic molecule.

However, interest in paracetamol was revived again during 20th century investigations performed to understand the mode of action of phenacetin. During one such study by Yale physiologists David Lester and Leon Greenberg in 1947 on the blood, plasma and urine samples of patients administered 1 g of phaenacetin, they reported that N-acetyl-p-aminophenol and its 'hydroxy conjugates' that is, sulfate and glucoronide conjugates were the major metabolites in blood and plasma. These conjugates are harmless and excreted through urine. No free aminophenol was detected in urine samples. Thus, they concluded that acetanilide is first oxidized to p-acetamidophenol and then to its hydroxyl conjugates.

 

Taking a clue from these reports, Bernard Brodie and Julius Axelrod, working in the New York University College of Medicine conducted their own experiments to confirm the analgesic action of acetaminophen. Further, they reported absence of formation of methaemoglobin after administration of paracetamol thereby supporting the safety of paracetamol as an analgesic and antipyretic drug. Finally, physicians started to recognize the safety of paracetamol and in 1955, McNeil Laboratories introduced TYLENOL Elixir for Children.

 Just like elsewhere in the world, Pacacetamol or more commonly, PCM remains a favourite analgesic and antipyretic medicine. All major pharmaceutical firms like Glaxosmithkline, Cipla, Abbot, Ipca, Ranbaxy, to cite a few, have their brands of PCM in the market. There are about 200 brands of PCM in the Indian market. According to a report, in 2019, the sales of all brands of paracetamol category were nearly Rs 530 crore. They touched Rs 924 crore by 2021. Dolo (Micro labs) is India's second most sold anti-fever and analgesic tablet, with a turnover of Rs 307 crore (in 2021). Crocin (Glaxosmithkline) is the sixth-largest, with sales of Rs 23.6 crore.

This is especially impressive for a molecule whose mechanism of action has still not been unequivocally established! Paracetamol 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. Recently some research points out towards the inhibition of cox-3 enzyme as a possible explanation for its analgesic action.