All About Advil

Open a random medicine cabinet, and there's a very good chance you'll see a bottle of ibuprofen. It's an extremely popular drug for pain and fever, evidenced by its 2019 worldwide use of more than 44,000 metric tons. More on that later.

First, a little history

1953 - At the Boots Pure Drug Company in the UK, two chemists began looking for analogs of aspirin that might be useful in treating rheumatoid arthritis.

1961 - Eight years and 600 compounds later, Stewart Adams (a pharmacologist) and John Nicholson (a chemist) filed a patent for 2-(4-isobutylphenyl) propionic acid, the chemical name for what would later become ibuprofen.

1969 - Boots launches Bufren, the first brand name of ibuprofen, for rheumatoid arthritis. It is available by prescription only. 

1970s  -  Additional indications are added for the drug, including pain and soft tissue injuries

1981 - An OTC version is launched.

1983 - Boots' patent for ibuprofen expires. Generic drug makers jump in.

1983 - Boots receives The Queen’s Award for Technological Achievement. By then, more than 100 million people in 120 countries have taken the drug. 

Time for some "math"

As I mentioned earlier, the annual production of ibuprofen is an astounding 44,000 metric tons. How many pills is this? I'll be damned if I'm going to try to figure it out (and I'd get it wrong anyhow), so ChatGPT seemed to be an excellent option to do the grunt work. Here's our conversation.

JB: How many 200 mg pills can be made from 44,000,000  44,000,000 metric tons of drug?

GPT: 44,000 metric tons of the drug can be used to make 220,000,000,000,000 (or 2.2 trillion) 200 mg pills.

(This doesn't look right, even to someone with appallingly poor math skills. So I asked again. And got a different answer!)

JB: Is 2.2 trillion correct?

GPT: My previous response contained a calculation error. I apologize for any confusion. 44,000 metric tons of a drug can be used to make 220,000,000,000,000 (220 trillion) 200 mg pills.

JB: You're an idiot.**

GPT: I'm here to provide information and assist with your questions to the best of my abilities. If you have any further questions or need clarification, please feel free to ask, and I'll be happy to help.

**Update 10/25: Thanks to reader Bob Thatcher the real idiot is yours truly because I asked GPT to do the calculation on 44,000,000 metric tons. In most cases, this is not 44 thousand.

D-U-H

Nonetheless, I still asked GPT to generate an image of Mozart if he were alive today.

It didn't do very well...

1. For pain: Lots of choices but little choice

Although there are plenty of different brands and generic versions, it all boils down to four drugs, three of which are useful. The first three are non-steroidal anti-inflammatory drugs (NSAIDs).

• Aspirin (acetylsalicylic acid, ASA, Bufferin...)
• Ibuprofen (Advil, Motrin, Nuprin..)
• Naproxen (Aleve, Naprosyn...)
• Acetaminophen (Tylenol) shouldn't even qualify as an analgesic drug because it is largely ineffective against pain, even though it is used for just this. Acetaminophen is not an NSAID.

Unfortunately, most NSAIDs, prescription or OTC, have similar side effects, primarily gastrointestinal, but also kidney toxicity and an increased risk of heart attacks. Aspirin, considered cardioprotective, doesn't carry the heart attack risk but has other downsides. It also causes GI problems (ulcers, bleeding) and increases the risk of a bleeding stroke because it is a blood thinner. The bottom line is that no NSAID will provide you with the best pain relief without potentially destroying your stomach, although Advil is generally considered to be a bit "kinder" in this regard than most of the others.

2. Drugs to avoid while taking ibuprofen

This is fairly simple. No other NSAID, prescription, or OTC should be taken along with Advil. NSAIDs need to be used very carefully with anti-inflammatory steroids, such as prednisone or methylprednisolone; the combination is tougher on the stomach than either drug alone. However, since Tylenol is not an NSAID, it can be safely taken with Advil and may even provide a boost in pain relief. People who have to be on an NSAID for an extended period can minimize GI side effects by also taking a proton pump inhibitor (e.g., pantoprazole. omeprazole) to reduce stomach acid, something I wrote about in more detail in 2018. See Which OTC Painkillers Can You Take Together?)

3. Ibuprofen is either one drug or two

S-Ibuprofen (left) is the active drug; the R-form is not pharmacologically active. But there is no point in separating them. In the body, the two forms are interconvertible, as indicated by the double arrow. (Can anyone guess how this happens?)

Because ibuprofen has a chiral center (the carbon with the red asterisk contains 4 different substituents), it can exist in two forms called enantiomers. (If you really want to torture yourself learn about enantiomers, see Carvone: One Molecule, Two Different Scents, And Flavors.) As is the case, almost universally, when a drug can exist in two enantiomeric forms, one is the actual active drug, and the other offers nothing except (maybe) toxicity or side effects. This is why, with few exceptions, the FDA will now only approve single enantiomeric, not racemic, new drugs. 

4. How does Advil work?

I won't go into the arachidonic acid pathway except to note that arachidonic acid, a critically important biomolecule, can be processed in either of two ways, depending on the enzymes that modify it  

Arachidonic acid is converted into leukotrienes by an enzyme called lipoxygenase and by another enzyme, cyclooxygenase (COX), into prostaglandins (1), a large family of potent hormones responsible for a wide variety of physiological responses, including pain and inflammation; this is why NSAIDs reduce pain and inflammation. Unfortunately, prostaglandins also play a part in protecting the stomach by stimulating the production of gastric mucosa. Unfortunately, if you block (red X) one effect you also block the other (2), and this explains why these useful drugs come with not-so-useful GI side effects. 

Probably a good time to stop. Writing this has given me a headache and GI distress. What to do? Time to pick my poison.

NOTE:

(1) The physiological effect of thromboxanes is beyond the scope of this article. 

(2) I have chosen not to go into drugs like Celebrex, which was designed to be a specific inhibitor of COX-2, one of the two isoforms of the enzyme. Inhibitors of COX-1 are more likely to cause ulcers, so Celebrex should (does?) go easier on the stomach. But not entirely. Here is a nice explanation of COX physiology, should be deranged enough to want to read it.