When I moved from Switzerland to the Netherlands, I anticipated that I would have to face some cultural differences at some point. I knew I would experience them, but I did not know what I would experience. My friends were concerned about the food (“But Dutch people only eat Gouda and drink milk during lunch time!”) and the people (“they are rude!”); I was more curious about how I would survive the Dutch rainy/misty/windy winters and whether I would miss the Swiss mountains.
The biggest shock I experienced was very far from this.
The biggest shock was paracetamol.
Paracetamol? Is this the name in Dutch of a food specialty from this country? Paracetam-Holland?
Let me tell you a story. One day, I had the brilliant idea to eat chicken thighs cooked on a disposable charcoal grill bought for 5€ at the local supermarket. “Cooked” is obviously an euphemism, as I realized two days later when I woke up with 40 °C of fever and the feeling my stomach was about to die, followed by my entire body. Sh*t, I thought (literally and figuratively), I have all the symptoms of a food poisoning caused by a bacteria. I need antibiotics. Let me call my GP. Oh wait – I just arrived in the country and I do not have a GP yet. Let me first die for three days to see if it goes better. Okay it does not and I lost already 5 kg. Why did I choose to move to a new country again? Okay this is not the moment to go into deep self-reflections; let me grab my phone and call the first GP I can find around.
Pfiuh, I was getting worried that you would not get the help you needed. So you called a GP and got some antibiotics?
No, I called the GP and got the following conversation.
Dr. Iza: Hi new GP, Dr. Iza here. I need your help; I got a food poisoning after having eaten undercooked chicken 5 days ago. My symptoms and the raw-chicken-story concur with a bacterial contamination; my condition is getting worse and I will need antibiotics.
GP: Oh, how annoying it is! Have you taken paracetamol already?
Dr. Iza: Paracetamol? Euh… Pardon, why would I take paracetamol? I do not have pain and the fever is caused by the bacteria. Can I have an appointment to get antibiotics, hmm?
GP: hmm nope. We don’t do antibiotics. We do paracetamol only. We suggest you take paracetamol and see in a couple of days if it goes better.
Dr. Iza (her nose twisting, a strong sign of getting angry): Dude. No. It won’t get better because I’M A PHARMACIST AND I KNOW I NEED ANTIBIOTICS TO GET RID OF THIS BACTERIA.
Long story short: it took me 10 days to eventually get antibiotics, and three weeks to be able to function again. My colleagues said I looked like a ghost when I came back to work.
Wow! But what’s this thing with paracetamol? Is that a substance with magical powers that can save the world?
Everyone knows paracetamol, and I can imagine that 99.99% of those who read these lines have already taken paracetamol in their life. If you live in the Netherlands, you will hear more than frequently “bah, just take some paracetamol and it will get better”. Hangover? Take a paracetamol! Period pain? Get some white pills! Flu-like symptoms? Oh, you’ll definitely feel better with 3-4 days of paracetamol!
But this is true, right? Everyone can take paracetamol, even children or pregnant women; it’s totally safe!
Here comes the trick: paracetamol has many benefits, yes. But it can lead to severe intoxications, and even death. Yes, death. And this is something that not everyone is aware of.
Death? No way! I thought it was not dangerous at all. Maybe you need to first explain us what paracetamol is and how it works.
Let me go back to the basics.
Paracetamol (that you may know as acetaminophen if you read those lines from the US) is the name of the chemical compound N-acetyl-para-aminophenol:
It was initially first synthesized in 1878 and introduced much later to the pharmaceutical market, in 1955, under the tradenames Tylenol Children’s Elixir (liquid form) and Panadol (tablet form). Paracetamol is largely used worldwide as analgesic (which means it relieves pain) and antipyretic (which means it prevents or reduces fever). Paracetamol is present on the list of essential medicine (22nd list, 2021) of the World Health Organization (WHO), a list which establish the medicines that – I quote – “satisfy the priority health care needs of a population” [1]. The WHO recommends the use of paracetamol for pain and palliative care, as well as against migraine, but not for anti-inflammatory use (as there are no proven benefits for this effect) [1]. To alleviate pain, paracetamol can be used either on its own for pain of low intensity or combined with other analgesics (including opioids) for moderate to strong pain.
What is interesting is that despite the fact it is used everywhere, we still have not elucidated fully all the biomolecular mechanisms that contribute to its effects.
Uffff is that the moment you will again gratify us with a very complex explanation on how a drug works in the body, using very complicated words?
No, because for today’s discussion this is not that important – as long as we’ve remembered so far that paracetamol is a first-line treatment against pain in adults.
Adults? You mean adults and children, as well as pregnant and breastfeeding women, isn’t it?
Correct, paracetamol can be administered to all these populations, and is usually well-tolerated. However, everyone will produce a metabolite called N-acetyl-p-benzoquinone imine (NAPQI) during the metabolism of paracetamol. Why is this important? Because this metabolite is toxic for the organism.
Let’s observe what happens in the body when someone takes a pill containing paracetamol. Similar to other drugs, paracetamol is first absorbed in the bloodstream via the digestive tract (in the intestines). From there, it is then distributed in the rest of the body, where it can provide the expected effect. Once paracetamol is present in the body, it will be also metabolized, i.e., be transformed into other chemical molecules that can be eliminated from the body (usually via urine). This metabolism happens mostly in the liver.
The metabolism of paracetamol produces mostly two metabolites, which are called paracetamol-glucuronide (5-070% of the metabolism) and paracetamol-sulfate (25-35% of the metabolism). These two metabolites do not have any activity or toxicity and are rapidly eliminated through urine [2]:
Besides these two metabolites, around 5-15% of paracetamol is transformed into NAPQI. NAPQI is a toxic compound that can bind to proteins present in the liver, leading to severe liver lesions and ultimately necrosis:
Luckily, at therapeutic doses of paracetamol, our organism has a great defense mechanism in place: it produces a compound called glutathione (GSH), which captures all NAPQI molecules and eliminates them from the body by complexing with them. This prevents the toxic effects of NAPQI on the liver:
However, if the dose of paracetamol is higher than the therapeutic dose, or in case of another conditions altering the liver, way more NAPQI will be produced. In turn, the production of NAPQI will exceed the capacity of detoxification of GSH:
If NAPQI is not removed from the liver anymore, it will attack the liver cells. If this happens, liver damages will become apparent 3-4 days after the ingestion of paracetamol, which may result in death from fulminant liver failure [2]:
Fulminant liver failure? Death? This sounds terrible! So what is considered “therapeutic dose” and which dose can lead to liver failure?
In adults, the guidelines recommend to use 500-1000 mg per dose, with 4-8 h interval between doses. The maximal cumulated dose is 4 g/day.
For children under the age of 12 years old, the dose is calculated based on the body weight, with a recommended dose of paracetamol of 15-20 mg/kg body weight per administration and 4-8 h interval between doses. The maximal dose is 60 mg/kg body weight per day [3].
Oral doses of 7.5-10 g/day of paracetamol in adults and 140-200 mg/kg body weight per day in children are toxic, with the development of liver and renal damages. Higher doses are lethal [2,3].
These doses are based on a healthy population but it is crucial to adapt them in specific populations who are at higher risks. In the last two decades, the number of patients suffering from liver toxicity due to paracetamol has dramatically increased in Europe and in the US – and this not only at higher doses, but also at therapeutic doses [2,4].
Adjusting the dose of paracetamol is essential in the following subpopulations [2]:
- Malnutrition (in the older population, for instance) and long fasting, which deplete the levels of GSH and increases the risks for an paracetamol overdose;
- Chronic alcohol abusers;
- Chronic consumers of paracetamol, who present slow but steady decline in GSH levels; or
- Patients taking medication that inhibits the metabolism of paracetamol into paracetamol-glucuronide (anti-epileptics) or induces a higher production of NAPQI (treatment for tuberculosis).
In these cases, the maximum dose of paracetamol per day should not exceed 2 g/day.
Wait – did you just say that consuming alcohol with paracetamol can lead to liver damages?
There is indeed a relation between a toxic effect of paracetamol and alcohol consumption, but only in excessive alcohol consumers, i.e., 140 g of alcohol/week in women and 210 g of alcohol/week in men (10 g corresponding usually to one glass of an alcoholic beverage, as we discussed in this post). In this case, an interesting effect happens [2,4]:
- In this population, the chronic consumption of alcohol increases the number of enzymes that produce NAPQI. Chronic users also typically show low levels of GSH, which overall results in a higher toxicity of paracetamol;
- But the acute/simultaneous consumption of alcohol with paracetamol seems to lead to a protective effect because both compete for the same enzyme, which lowers the production of NAPQI.
I know, this is not easy to understand. This is even more complex to understand as this interaction also depends on the nutrition status of the patient, the alcohol consumption pattern, and other aspects influencing the liver condition of these patients [4].
But what about normal consumption of alcohol, then? Should I worry if I take paracetamol for the headache I got after a night where I drank too much wine?
That is exactly where it starts to be difficult to establish clear guidelines. Based on the literature currently available, there is no evidence that combining therapeutic doses of paracetamol and “a bit of alcohol” is toxic for the liver. However, remember the numbers I mentioned when I referred to “excessive alcohol consumption”: as a woman, drinking two small glasses of wine per day (i.e., two times 10 cl, which is equivalent to 20 g of alcohol per day) adds up to 14 small glasses of wine per week, which reaches the cut-off that would make me a “excessive alcohol consumer”. For a man, this would be the same for three glasses per day. Many people would not consider these numbers as excessive, but in this discussion they are.
I would therefore refrain drinking alcohol when taking paracetamol, or sticking to one glass only (or even less, depending on your sex and other conditions). Similarly, I would refrain from taking paracetamol during periods where my consumption of alcohol is above zero.
Taking paracetamol usually means your body is not in balance anymore. Drinking alcohol does not bring any benefits to this (as we have already seen in the same post on alcohol) – it may even slower your recovery. My own advice? Give your body some rest if it is the case, and refrain from drinking alcohol until you are better again. Your liver will be grateful.
What if I unintentionally took too much paracetamol and reached the toxic doses?
Call directly the emergency unit at the hospital. An antidote to paracetamol overdose exists, called N-acetylcysteine. It can save lives.
And remember, it is not because paracetamol is so readily available and present in everyone’s home that it should not be taken with precautions – and an informed mind.
Dr. Iza
References:
[1] WHO model list of essential medicines – 22nd list, 2021. https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2021.02 (accessed 15-12-2022)
[2] M. Seirafi, A. Iten, A. Hadengue, Paracétamol: toxicité hépatique aux doses thérapeutiques et populations à risque. Rev Med Suisse 3 (2007) 2345.
[3] Compendium.ch, BEN-U-RON supp 250 mg enf., information professionnelle. https://compendium.ch/product/4123-ben-u-ron-supp-250-mg-enf/mpro#MPro7150 (accessed 18-12-2022)
[4] S.M. Riordan, R. Williams, Alcohol exposure and paracetamol-induced hepatotoxicity. Addict Biol 7 (2002) 191.
