The "next Purple Pill". Supposedly a more powerful successor to Prilosec, this relatively new medication (esomeprazole magnesium) by AstraZeneca relieves heartburn and prevents erosion of the esophagus caused by acid reflux disease (a malfunction of the lower esophageal sphincter which repeatedly permits stomach acid to churn up into the esophagus).

Nexium is supposedly superior to its predecessor because it is Prilosec which has been refined to include more of the part of the medication that actually works. Or something like that.

Supposedly. According to my gastroenterologist, the medicine does seem to work marginally better than Prilosec did. But he says it's because in practice the dosage in which Nexium is manufactured is larger than that of the other pill, so the stomach is getting more of the medicine.

It turns out Prilosec was losing its 17-year patent and generic drug makers would soon be given the right to create a generic form. So our friends at A.Z. decided they'd better slightly rework and rebrand their hot-selling item in order to be able to acquire a new patent. That way they can keep their lead in the market and keep the cash cow injected with BGH. Gotta love the pharmaceutical companies. It's all about the money, my esophagus be damned!

Nexium is a brand name for S-omeprazole, a drug that reduces gastric acid secretion, of the British-Swedish firm AstraZeneca. It is used to treat peptic ulcers, duodenal ulcers, and to relieve acid reflux (heartburn) symptoms, such as erosive esophagitis. It is a proton pump inhibitor, which works by decreasing stomach acid secretion.

AstraZeneca already had an omeprazole product in the market, namely Prilosec, and its competetors sold omeprazole analogues. Now, the analogues of omeprazole itself are not more or less effective, and there is no reason to choose one over omeprazole, so no company had an edge over other.

But, omeprazole is an chiral compound. That is, there is an atom, called chiral center, with four different substituents on it. This makes it necessarily asymmetric. If you change the places of two substituents, it will no longer be the same molecule, but its mirror image, or another enantiomer. This may not seem like a big deal, but in the human body, the places where the molecule binds to are similarly asymmetric. One enantiomer of omeprazole, namely the S-enantiomer, works. The other, namely the R-enantiomer, just sits there, and contributes to the side effects, so it's not actually just inert, but counterproductive. It also forces the manufacturer to waste half of the precursor chemicals, since without special steps, both S-, and R-forms are produced equally, which is called a racemic mixture.

So, the people at AstraZeneca figured out, if you selectively produce only S-omeprazole, you can give twice the dose "for free", without twice everything else. More importantly, the omeprazole patent was into expiring in 2000, so they could re-patent, re-market and re-set prices for the same omeprazole by developing an enantiopure product. And that they did. The enantiomer was patented, "The new Purple Pill" campaign was launched in the USA to encourage people to switch from the racemic Prilosec to the enantiopure Nexium, and the price was set considerably higher. A course of Nexium (40 mg) costs a bit over 2 € per day. (Someone could provide a dollar figure.)

Nexium is more effective than its racemic competetitors only by a thin margin, and even the existence of this margin has been "controversialized", although individual patients say there is an improvement. A curiosity of marketing is that they also renamed the S-enantiopure omeprazole to "esomeprazole", which sounds like a different chemical, while it's only a purer form of the same chemical. Yet it's a baseless claim to say that AstraZeneca is just "ripping off", since the ability to double the dose "for free" is an improvement.

Nexium is in pills, which absorb water and burst open soon after being wetted in acid, to release tiny enteric coated pellets. Although there is no proof that this is better than simply coating the entire pill, it does reduce the annoyance of swallowing pills. It appears to me that the disintegration is catalytic in acid: plain water does not work, but adding few drops of apple juice will do the trick in seconds. The released pellets, about half a millimeter in size, are stable in the acidic stomach, but disintegrate in the non-acidic small intestine to release the omeprazole. Enteric coating is needed, because omeprazole converts to its insoluble form in acid, and is thus incapacitated.

The patient should not take antacids (chemicals that neutralize acid) with Nexium, because the neutral-to-basic environment dissolves the enteric coated pellets, and when stomach acid is secreted again, the omeprazole is incapacitated. On the other hand, the Nexium course is not a contraindication to antacids, since after the omeprazole has absorbed, antacids can be taken again, and omeprazole absorbs and does its trick in a matter of hours.

Its mechanism of action is proton pump inhibition. The cells which secrete stomach acid do it by pumping protons (acid ions) to the stomach. In their cell membranes, they have enzyme proteins called proton pumps, which pump the protons (that is, the acidity) to the stomach. These are ideal targets for medication, because they are ultimately responsible for the secretion of stomach acid. S-omeprazole irreversibly and specifically binds to these pumps, incapacitating them. It takes very long, about 24 hours, for the cells to synthesize new pumps. This is why a single pill a day can be effective. This is also the reason one should take the pill about one hour before the first meal: when one begins eating and thus starts the secretion of stomach acid, the maximum number of pumps are incapacitated and secretion minimized.

Because omeprazole does not act directly, but indirectly by inhibiting proton pumps, its full effect of inhibition doesn't kick in immediately with the first dose. Rather, it takes a couple of days to pile up. Its effective utility is only 64% first, but if repeated, it rises to 89%. Omeprazole is absorbed fast, and it achieves its peak concentration in blood in 1-2 hours. Its half-life is only 1.3 hours in the blood, and it is completely eliminated from the body each day. Its metabolism takes place in the liver, which converts it to a form that is excreted in urine. As already noted, the short retention time does not make a difference, because it is specifically bound to the proton pumps until new ones are synthesized. It is not necessary to continuously maintain its concentration in blood, as with histamine receptor inhibitors such as ranitidine (Ranimex) or famotidine (Pepcid).

The dose is 40 mg per day for acute, serious peptic ulcers. Paradoxically, the same dose but divided in 20 mg twice a day is used for maintenance treatment of chronic disease.

The form the drug is given is inactive, but it is soluble to lipids (fats), and it can easily go through cell membranes, which are made of lipid (phospholipids, exactly). When it reaches an acidic environment inside the cell, it is protonated and rearranged into its active form. This form binds covalently to the proton pump (by an irreversible chemical reaction, that is). Should you break the enteric coating in the capsules, you expose the drug to acid, which protonates it and disables it from passing through the cell membrane.

Since it's for reducing stomach acidity, any drugs that depend on stomach acidity for absorption don't absorb well. Since it is metabolized by a specific enzyme in the liver, namely CYP2C19, drugs that depend on it for elimination, such as benzodiazepam, are retained longer, and a smaller dose of these drugs is needed. Liver insuffiency causes longer retention times for Nexium, but it is not necessary to change the dose, since it will be completely eliminated anyway if taken once a day.

Side effects are rare, found only in 10-1% or less of patients. These include upset stomach (abdominal pain, diarrhea, flatulence, nausea, vomiting, constipation) and headache. Less common effects are rash, itch, vertigo, dry mouth, and urticaria. Rare symptoms are severe allergic reactions and symptoms of the nervous system, such as tactile hallucinations, lethargy, vertigo and insomnia. Other such effects are confusion, anxiety, aggression, depression and hallucinations, which are typical of severely ill patients. The effects of aggression and anxiety are particularly problematic, if the ulcers are stress-induced, since the stress response includes an increase in stomach acid secretion.

Chemically, omeprazole is moderately complex, but not very complex. It consists of substituted pyridinyl and benzimidazole groups bound at a chiral sulfinyl, also known as sulfoxide. Sulfinyl is sulfur with oxygen double bonded to it, and it takes two substituents. The "chiral" bit means that it is center of asymmetry; changing the places of the substituents makes S-omeprazole into R-omeprazole, and vice versa, and that in this preparation, it is exclusively the S-enantiomer. The pyridine ring or a pyridinyl group is an six-membered aromatic ring like benzene, except with one nitrogen atom instead of a carbon in the ring. In omeprazole, this nitrogen is at the ortho position (next to the sulfinyl bond). On the other side of the ring with respect to the nitrogen, there are three substituents: two methyls (-CH3) at the ortho and para positions, and a methoxy group (-OCH3) at the meta position between them. An imidazole group has a carbon in the center, and two nitrogens connected to it (-C(=N-)(-NH-)). One is by a double bond, one by a single bond; the single-bonded nitrogen has also a proton. Benzimidazole is an imidazole connected to a benzene ring by both of these nitrogens, giving a five-membered ring fused with the six-membered benzene. In omeprazole, the benzene ring has a methoxy substituent at the para position with respect to the single-bonded nitrogen.

Here is an ASCII art attempt at the chemical structure. The rings inside the rings denote an aromatic system. Notice that the sulfinyl has a 3-D chiral configuration that can't be drawn in 2-D ASCII art. The pyridinyl should be facing away from the viewer, while the electron pair (denoted with ':') out from the plane.

:         OMe     methoxy (OCH3) at meta
:         |
:    Me   C   Me  methyls (CH3) at para, ortho
:      \ / \ /
:       C _ C
:       |(_)|     pyridinyl ring
:       C   C
:        \ / \
:         N  :S=O sulfinyl
:            /
: imide   N=C     \
:        /  |     |
:       C   NH    |-imidazole part of benzimidazole
:      / \ /      /
:     C _ C
:     |(_)|       benzene ring of benzimidazole
:     C   C
:    / \ /
: MeO   C

Nexium does not offer immediate help, and it does not cure you, since peptic ulcers are only a symptom of something else. But, it stops your body from aggravating the symptoms, and allows you to heal. If the formation of peptic ulcers is induced by stress (and not as a side effect of a NSAID painkiller, for example), one should find out and eradicate the behaviors leading to anxiety. A self-supporting positive feedback loop can form, when anxiety causes heightened sensitivity to pain, which increases the stress response to the stomach pain, which causes more anxiety, which causes more excessive acid secretion.

Disclaimer: This text is not written by a medical professional. Seek treatment from and follow the directions of a medical doctor should any symptoms occur.

Nexium is a prescription medication used to treat gastroesophagal reflux disease (or heartburn, as it is more commonly known). It does this by inhibiting a proton pump, or in other words, by stopping the stomach from secreting stomach acid. By many reports, it is quite good at that, and has relatively minimal side effects. Although heartburn might seem like a minor condition, it can become quite serious if untreated, so Nexium can be a quite important medication.

The two above writeups covered much of the pharmacology of Nexium, and I thought they covered everything that needed to be said on the matter. But by serendipity, right after reading them, someone posted about HeadOn, a chapstick like medicine that suggests, without stating, that it cures headaches, even though it provides no mechanism for doing so. This inspired me to write a little bit on the economics and sociology of Nexium.

Nexium is, as of 2013, the second most prescribed drug in terms of sales and the 5th most prescribed drug in terms of units. Yearly sales of Nexium in the United States ran to 5.97 billion dollars, which is greater than the GDP of Liechtenstein, and thus of 44 other independent countries with a GDP less than that of Liechtenstein. 5.97 billion dollars is also 50% greater than the cost of a Nimitz Class Aircraft Carrier. It is enough to buy eight B-2 Stealth Bombers, and is more than twice the cost of the Curiosity rover program. I could come up with more examples, but the point that 6 billion dollars is a lot of money doesn't need much embellishment.

As was mentioned in the above write-ups, Nexium is a derivative of Prilosec. Prilosec is a drug with the same indications and action as Nexium. The difference is that Nexium is one of the specific isomers contained in prilosec, which is a mixture of slightly different forms of the same structure. The Nexium form is the most active (or only active form), so by taking it, you get the same effect with a smaller dosage. But that leads to the question of how much difference their is between taking a certain dose of Nexium and the same dosage contained in Prilosec. And that question has been answered,through a scientific study: after five days of treatment, Nexium had shown a benefit in 68.4% of patients, versus 62% of patients who were taking Prilosec. That means that if you have a group of sixteen patients, 10 of them will show a benefit from Prilosec but 11 of them will show a benefit from Nexium. Although this is statistically significant, it is probably not therapeutically significant for most patients.

With this rather narrow difference, there are a lot of questions about why exactly Nexium is so popular. The obvious answer is that the company that owns the patent on Nexium (Prilosec being out of patent) has marketed quite aggressively both to the public and to medical professionals. It is not cynical to take this as an example of how marketing has corrupted the practice of medicine, and not in a small degree either: 6 billion dollars a year is, as stated, a lot of money.

The 6 billion dollar figure also only covers the direct cost of the medication. Nexium, despite having the same effects, the same side-effects, and the same toxicity, is a prescription drug, while Prilosec is an Over The Counter medication. This means that Nexium has added costs, the cost of needing to visit a doctor and get a prescription. So we can imagine parallel circumstances: someone with a full time job with health insurance sees a commercial for Nexium, and decides to ask their doctor about it. Meanwhile, someone who works in an uninsured job or otherwise has no health insurance sees an ad for Prilosec (featuring, in a demographically telling moment, Larry the Cable Guy) and goes down to the local Walgreens and buys some Prilosec. Ironically enough, the first person has been rewarded with resources that can only be exchanged for something that is symbolically better than what the second person has. It is situations like this that make the already confusing debate about health care costs even more confusing, because there is an undeniable symbolic and psychological element in how people use pharmaceuticals.

There is no problem with Nexium: it seems to be a useful medication without many downsides that can treat a serious condition. On the other hand, the success of this medication leads to many questions about the economic costs and benefits of prescription medications.

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