With the FDA approval yesterday of Teva’s generic Lexapro (escitalopram) I’m taking this opportunity to remember my years as a chemistry major at Bowdoin College and talk about a subject that is fascinating and not really that complicated. The movement toward the use of isolated isomers (also called sterioisomers or enantiomers ) as medication seems to be an accelerating trend in recent years.
A compound is defined by its chemical structure. The number of each type of ato, and the bonds between the atoms define the compound. For many drugs every molecule is shaped the same. For others the shape of the molecule can assume mirror image conformations, i.e. a left-handed and a right-handed shape. In medications the useful isomers are those with an asymmetric (chiral) center where there are two mirror image options for the shape of the chemical bonds to assume. These are technically called enantiomers, but are most commonly called R and S isomers. S stands for the Latin “sin” for left, R for the Latin rectus for right. (There are two other nomenclature methods for designating isomers, one using +/-, another using D/L, but these are seldom used in medicine and are mentioned so if you see them you won’t wonder if I am making all this stuff up.) A mixture of both the L and S isomers is called a racemic mixture. The FDA has developed a detailed approach to isomers that makes an interesting read for those of you with a scientific interest.
The way most drugs work in the body is that they attach to a receptor site. If the receptor site is shaped in way that the left or right handed molecule fits well, and the other shape does not fit well, the one that fits well is going to the active drug. Think of this like hands and a glove. Your right hand fits nicely into a right-handed glove. Your left hand does not easily fit. The same is true for your left hand and a left-handed glove.
For other things like your head, any hat the right size fits because our heads are symmetric (relatively), with no isomeric variations.
In some cases the less active isomer is truly inactive. In other cases it appears that the “pure” active isomer has advantages as a medication. The not-so-surprising observation that drug companies somehow seem to discover that one isomer of their blockbuster drug is really the active isomer just before the patent expires on the original isomer mix leads some of us to be skeptical about the benefits of isomers. Still the trend toward isomers as medications seems to be real, so it is useful to understand what an isomer is, and why sometimes it may not be worth the added expense of buying the brand name isomer when the isomeric mix product is an inexpensive generic. Here are a few of the more popular isomers used as medication with a little Dr. Pullen commentary:
Lexapro vs citalopram: Lexapro was brought to market by Forest Laboratories just prior to the patent expiration of Celexa, the racemic citalopram product. The argument that Lexapro has less side effects and works faster is much harder to define than with a product like Nexium where more objective endpoints like ulcer healing, gastric pH, etc are available, but in my experience most patients to equally well on generic $4./month citalopram vs. Lexapro at $138.24/ month (Costco pricing). With the approval of Teva to exclusively market generic Lexapro for 6 months their price will be somewhat lower than brand name Lexapro, but in 6 months expect much lower prices from competitors. If the price approaches the $4. cost of citalopram generic Lexapro is likely to be very commonly used.
Nexium vs Omeprazole: Nexium has been a blockbuster drug for AstraZenica for years. This was a brilliant marketing move, by AstraZenica, again just prior to Prilosec (the original brand name for omeprazole) going generic. In order to market a “better” drug, Nexium was marketed as a 40 mg esomepraxole (left handed isomer) and compared to the 20 mg dose of omeprazole. It was shown to be very slightly faster acting. Now that you understand isomers does it surprise anyone that by taking the active isomer or omeprazole and using 4 times the dose of esomeprazole that is in racemic omeprazole the it is slightly faster acting? Not me. Is it worth the cost premium (Costco omeprazole 20 mg = $11.75/ 30 capsules vs. Nexium 40 mg = $202.75 / 30 capsules). Probably never.
Albuterol vs Xopenex: Unlike the prior two isomers, Xopenex is the R isomer not the S isomer of albuterol. There are some patients where the racemic mixture in albuterol causes more cardiac stimulation like racing heartrate than the R-albuterol isomer in Xopenex. This makes Xopenex preferable for some patients, but most patients do just fine on albuterol.
There are lots of other drugs sold as isomers, but this is enough to give you examples, and hopefully enough reason to be skeptical of claims of superiority for isomers sold as new expensive branded drugs.