gms | German Medical Science

Results: Lay consumers tend to believe that old, approved and OTC-available drugs are safe and effective. They wonder why these old drugs are so well-tolerated whilst many newly developed compounds fail in the clinic. Their assumption that old drugs are safe is rarely founded by scientific evidence. A few years ago we learnt that clobutinol (Silomat), which was in use for many decades as antitussive drug, turned out to carry unpredicted and so far unknown risks. Accidental research led to the elimination of clobutinol. Recently paracetamol, the most widely used drug of the world, was observed to be not a unique analgesic but a compound which interferes with the production of prostaglandins as many analgesics do. Based on this finding we and others could show that paracetamol goes along not only with the well-known liver damage but GI, kidney and cardiovascular toxicity, as more modern cyclooxygenase inhibitors do.

It is amazing to realize that the precursor of paracetamol, acetanilide, left the market after a few years of use about a hundred years ago due to methemoglobinemia. It was supplanted by phenacetin, the mother-substance of paracetamol, which was removed after it turned out that it contributed to lethal interstitial nephritis. It came in handy that the main metabolite of phenacetin, paracetamol, appeared slightly less toxic. It took almost 20 years until the first reports on acute, lethal liver failure due to paracetamol appeared. Moreover, recent evidence demonstrates that paracetamol works poorly if at all but shows all the problems of cyclooxygenase inhibitors. In addition, it is likely to cause asthma and developmental deficits in children from mothers who took paracetamol during pregnancy. On this background one wonders if such an old, widely used drug is safe and deserves to remain in human use. Acetanilide, phenacetin and paracetamol, as we know today, produce a toxic metabolite, NAPQI, which cannot be avoided and would if paracetamol was to be considered today for market admission, turn out an insurmountable obstacle.

Conclusion: Consequently, old drugs need to be investigated toxicologically as cautiously as a new compound. As long as we close our eyes on old drugs more than thousand people will die every year from paracetamol toxicity.