Paracetamol’s mystery unfolded as researchers identify blood vessel metabolism

Pamol, Panodil, Panadol, Tylenol – there’s a good chance you have paracetamol at home. The drug is undoubtedly one of the most widely used over-the-counter drugs worldwide, where it is often used to treat mild to moderate pain including headaches, toothaches and sprains. However, how the drug delivers its pain-relieving effects is still unclear.

Despite not fully understanding how paracetamol relieves pain, it can be administered directly to the bloodstream in critically ill patients in the hospital. It is in this clinical setting where it also causes trouble for health professionals. Although excellent at relieving pain, when given directly into the veins of critically ill patients, paracetamol can cause a dramatic drop in blood pressure, which can be fatal.

Now, researchers at the University of Copenhagen have made an important discovery about paracetamol, which they hope will lead to safer use of the drug in hospitals. Associate Professor Thomas Jepps, senior author of the new study, explains:

"We discovered that paracetamol can be broken down in the walls of blood vessels, not just in the liver as previously thought. Our findings show that the arteries can break down (metabolize) the drug when given directly into the bloodstream and this creates a chemical that is very good at making your blood vessels relax, which would cause a drop in blood pressure,” says Thomas Jepps at the Department of Biomedical Sciences.

Dangerous drop in blood pressure

The mechanism by which intravenous paracetamol causes a dangerous drop in blood pressure in critically ill patients was previously unknown, albeit widely reported.

“We show, for the first time, how paracetamol can be metabolized in the blood vessel wall thereby creating another chemical (a metabolite) that can cause the arteries to relax, thereby causing this drop in blood pressure,” says Thomas Jepps.

While this might sound technical, it could lead to tangible implications for critically ill patients.

As of now, nurses must closely monitor the patient’s blood pressure and are occasionally required to administer drugs to rescue the patients’ blood pressure before it drops too low, which can be catastrophic for the patient.

“Understanding this side effect of paracetamol is crucial. It means that we can develop new tests or more specific drugs to counteract this side effect of low blood pressure in patients who need intravenous paracetamol,” says Thomas Jepps.

The metabolism of paracetamol

The researchers at the University of Copenhagen conducted a series of experiments to investigate the metabolism of intravenous paracetamol.

They treated cultured human cells from the blood vessel walls with paracetamol and discovered that these cells could produce an important metabolite responsible for the drug's pain-relieving effects as well as the blood pressure drop.

“We then infused rats with paracetamol and observed the drop in blood pressure, similar to the effect reported in humans, and we confirmed the drop is caused by the metabolism of paracetamol in the arteries rather than the liver,” says Thomas Jepps.

It is important to stress that this side effect of paracetamol is not observed when taken orally and at the recommended doses. However, this latest study does raise the interesting possibility that some of the pain relieving effects of paracetamol are caused by local metabolism outside the liver. Looking ahead, the team are planning to investigate whether paracetamol taken orally is also broken down in the blood vessels, hoping to further understand how the drug works.

And, sometimes, the most necessary funding does not come from outside the university walls. This study was funded by an internal departmental collaboration grant from the Department of Biomedical Sciences. The grant encourages cooperation between different sections and allowed several groups to combine their expertise to investigate the metabolism of paracetamol.