Hey Chill, bad news buddy. The store didn’t have any orange juice. Aww, that’s too bad. But hey, I got you, come on. I got you uh… grapefruit juice. Oh okay well… You boys talking about grapefruit? It’s crazy how it can make you overdose like— Oh no, don’t ruin another— Today’s episode concerns pharmacology and describes an overdose. As always, we recommend speaking to medical professionals if you have any further questions. And with that out of the way, let’s get into it! A 42-year-old woman with a history of migraines was admitted to the hospital after 2 weeks of headaches, nausea, and altered sensorium—that is, she could not think clearly or concentrate. She’d been taking the drug Fioricet to manage her migraine symptoms in addition to four other medications her doctor had prescribed that she was taking daily, including verapamil, a blood pressure medication used to treat angina and migraines. She was barely responsive when she arrived at the ER, and they found her to have a complete heart block, which is when the electrical signals from the top of the heart cannot pass to the bottom. Suddenly, she went into respiratory failure, so doctors scrambled to intubate her and put her on a ventilator. The first thing that medical staff checked was whether or not this was a street drug overdose, which was quickly ruled out. They checked her Verapamil level, and discovered that it was five times as concentrated than the regular dose. She had improved dramatically over the course of two days and was weaned off the ventilator. Once she’d recovered, she denied that she had taken any more than a double dose of Verapamil which she took accidentally the morning of her hospitalization. This was strange, because the amount of the drug in her bloodstream indicated that she should have taken significantly more. Oh, there were more drugs in her system than she told them? Everybody lies. She was telling the truth though. Medical staff corroborated this by checking the amount of pills left in her medicine bottle, and cross-checked it with her pharmacy for dose and strength of the pills. In addition to that, doctors couldn’t find any significant relationship between Verapamil and any one of her other prescription medications. The woman, after more questioning by medical staff, admitted that she had been feeling nauseous up to the day she was admitted to the ER. To deal with this, she had been drinking grapefruit juice, about 3-4 litres in the 7 days prior to her admission. Something about the grapefruit had multiplied the level of Verapamil in her bloodstream from an accidental double dose, to 5 times the adequate therapeutic limit. It’s not just Verapamil though. Another woman had been taking antidepressants along with another blood pressure medication called Procardia, and keeled over dead while vacuuming. A young man from Michigan died after taking an antihistamine called Seldane. The thing they had in common? They both drank grapefruit juice at the time they were taking their medications. We first figured out that something was going on with grapefruit back in 1998. Researchers took 6 healthy men, and 6 men with hypertension, and had them take a drug to lower blood pressure with water, orange juice, and grapefruit juice. They then measured any adverse reactions and found that combining grapefruit juice with this particular medication led to a 50% increase in headaches, facial flushing, and lightheadedness. Further testing shows that the grapefruit had tripled the bioavailability of the drug researchers had given the subjects. Wait, bioavailability— what’s that? Well, Chill. Bioavailability is how much of any active ingredient enters your system, the amount of drug that your body can’t filter out. Any substance you consume orally will be absorbed by your small intestine, passed through your liver, and then into your bloodstream like everything else that you eat. Both the small intestine and the liver metabolize many drugs, breaking them down, so not all of the active ingredients you consume orally actually get into your bloodstream. This is called the “first pass” effect. Other methods of introducing a drug into your system, such as intravenously, do not have to pass through the liver, and therefore are not subject to the “first pass” effect. The main force behind the metabolization of substances in the small intestine and the liver is an enzyme called Cytochrome P450 3A4, shortened to CYP3A4. CY345—what now? Scientists are bad at naming things, I’m… I’m sorry. But the bioinactivation of about 50% of all drugs is caused by this enzyme. Basically it will break down half of all the drugs that pass through your gastrointestinal system. This, and other enzymes, are behind that “first pass” effect I mentioned earlier. However, when this enzyme is inhibited, that “first pass” becomes a chemical “fast pass”. Inhibi-what? Use English. When the enzyme CYP3A4 is “inhibited”, it means that something is keeping it from doing its job. CYP3A4 keeps certain things out of your body by breaking them down and excreting them, it works kind of like a firewall for chemicals in your body. But if it were “turned off” for some reason, less of the substance would break down, and more would end up in your body. In this case, it’s more of the active ingredient of any particular drug than the dosage requires. Grapefruit contains a chemical called Furanocoumarins which inhibit CYP3A4, leading to higher concentrations of any particular chemical in your bloodstream. But wait, how can foo um… Fooroocoomoo— Furanocoumarins. I don’t like it either. Yeah, how can... that, make you have more drugs in your body? The bioavailability of any particular drug can vary greatly. Which is why it’s so important to take any medication you’re prescribed properly. Pharmaceutical scientists design products so that just the right amount ends up in your system. For example, the oral bioavailability of the drug felodipine to treat high blood pressure is about 15%, so approximately 85% of the active ingredient isn’t getting past your liver. So you can imagine the trouble if suddenly that weren’t to happen, and you got 100% of the entire dose. In fact, felodipine taken with grapefruit is 3 times as concentrated than when taken with water. Felodipine lowers your blood pressure, so you’d probably experience headaches, dizziness, and maybe faint, but grapefruit reacts with more than just blood pressure medication, and not all drugs are as benign as that at high doses. Wait, so how much grapefruit is too much then? Unfortunately one whole grapefruit, or 200 milliliters of juice is enough to increase drug concentration and worsen any negative effects. Not only that, grapefruit isn’t the only food to contain Furanocoumarins. It’s also found in Seville oranges, limes, and pomelos. Wait, wait, o-oranges? Oh no— Oh no! No, not all oranges buddy. Sweet oranges, like navel and Valencia don’t produce this reaction! Oh thank goodness. I’m gonna have to meditate for hours to work through that trauma. So if I drink grapefruit juice, how long do I have to wait before it’s safe to take my medicine? Or you know, drink a energy compound yet-to-be approved by the FDA? Well researchers found that grapefruit consumed 4 hours before orally ingesting Felodipine produced the maximum effect. After 10 hours the effect reduced to 50%, and after 24 hours the effect was only decreased to 25%. Not only that, but grapefruit consumed repeatedly generates a cumulative response. So if you need to take medication every day, any fruit with Furanocoumarins might be off the table altogether. Oh okay. But do we know which medications react? That’s a hard question. The short answer is yes, but our data isn’t comprehensive. In all likelihood there are probably many more drugs that are impacted by Furanocoumarins. It’s an important question though. Your doctor is trained to know what substances do what to the body, and how those substances interact with each other. Like how alcohol and ibuprofen can lead to stomach bleeding and ulcers, your doctor needs to know your medical history to ensure you don’t experience any adverse effects. Moreover, learning the ins and outs of the underlying systems behind drug interactions, can allow us to foresee issues like the grapefruit effect before they happen. Pharmacists are also trained to recognize drug interactions, and they more often than not catch mistakes doctors make. Yeah that’s fine and dandy, but what do I do with all this poison that I bought? That’s a bit dramatic. Grapefruit isn’t poison, you just need to check with your doctor to make sure you’re safe to eat grapefruit. If you’re not on any regular medications, then you’re probably fine. Oh good! Like epidemiologist Mark Haden has said, “Any drug can be used for benefit or harm depending on the context of use”. And that goes for pretty much everything, really. Working out every single day with no breaks can hurt you, even though being physically active is good for your health. Going out to eat once in a while can be good for your mental health, but it’ll hurt your wallet to do it all the time. It’s all about how you consume. A tall glass of grapefruit juice is perfectly safe, just like taking an ibuprofen for a headache is safe. But if you’re doing things recklessly, you can do some serious damage to your health. We’re learning more every day, and the best thing we can do as individuals is to educate ourselves on what we’re putting into our bodies. Read the label on the bottle, ask your doctor questions, and do your own research, and please use reliable sources when doing so. Hey, hey Brew! The gang was wondering if we’re still down to play Among Us tonight. Oh, sure thing! Be there in a second! Solving mysteries is literally my day job. Oh snap. Oh goodness no!
