Beta blockers and genetic variation

It's happening again.
I'm sitting in a meeting, and suddenly I feel my hands prickling. My heart thumps faster. I can't concentrate on what people around me are saying. My head is buzzing, and cold sweat trickles down my neck. I feel the tingling of panic biting at the tip of my fingers. My muscles tense, adrenaline spikes. Every cell of my body screams, "Danger!"

Now, part of me wants to take out my notebook and jot everything down for my next high-adrenaline, action-packed story.

The other (more sensible) part of me, wants to run out of the room, pick up the phone, dial my doctor's office number, and yell, "I NEED THE BETA BLOCKERS AGAIN!!!!!"

In case you didn't know, beta blockers are a wonderful drug. I'm told you can't take them during Olympic competitions, but that's okay, I've given up my Olympic dreams a long time ago. They are considered performance enhancers because they fend off the action of adrenaline and hence prevent stage freight and all sorts of anxieties. In other words, they make you happy. Olympics aside, they are prescribed in clinical cases with a high risk of infarction myocardial ischemia, or, as in my case, when the thyroid acts up and starts producing too much thyroid hormones. (I've actually been feeling really well for the past year, knock on wood!)

They block the beta-adrenergic receptors (hence the name), which are the receptors that are stimulated by adrenaline, the hormone produced by the adrenal glands. When adrenaline is released, it binds to the beta-adrenergic receptors and this causes a bunch of things to happen: the heart starts pumping faster in order to better oxygenate the muscles; blood flow is diverted from non-essential organs to the muscles; pupils and airways dilate; vessels narrow. Basically, the body is getting ready to "either fight or flight."

So here comes the beautiful, casually charming and nonchalantly laid-back, beta-blocker -- our hero. He sits right on the receptor and when the adrenaline comes, he smiles, puffs out some smoke, and, talking around a charred cigarette butt, says, "So long, babe. Spot's taken."

Yeah. Been reading too much Chandler.

I've been quite happy with beta-blockers, though my problem was not of a cardiac nature. So, I was quite surprised to find out that

"Recent evidence suggests that there is substantial inter-individual difference in how patients respond to beta-blockers: Some patients experience strong side effects such as excessive hypotension and bradycardia, whereas others experience no measurable response. Several lines of evidence suggest that the individual genetic background is responsible for these observed response differences [1]."

In order to understand this, one needs to understand how drugs are metabolized within the body. A cytochrome enzyme is an enzyme involved in the canalization of organic substances, and, as a consequence, in drug metabolism. The enzyme responsible for the metabolism of most beta-blockers is, CYP2D6. Now, here's the interesting part: the corresponding gene shows a large variability due to genetic polymorphisms (any variant that's at least 5% prevalent in the population). In other words, different individuals may present different alleles, and the frequency of these variants varies across ethnic groups. In [1], Nagele and Liggett discuss the most important SNPs and gene variants within adrenergic receptors and CYP2D6 and their possible effects in the metabolism of beta-blockers. They go in far more details than I want to here, so I'll limit myself to highlight the importance of their review: it turns out that patients with cardiovascular risk factors can suffer from potentially fatal complications after noncardiac surgery, and for that reason beta-blockers have been used as a preventive treatment of perioperative infarction. In this context, it is relevant to be able to predict the drug response based on the patient's genetic variation. Beta-blockers can indeed lower the risk of perioperative MI and cardiac death, but also carry a substantial risk for adverse cardiovascular side effects, such as hypotension and bradycardia. Given that genetic variation in CYP2D6-dependent metabolism and adrenergic signaling may affect the outcome, the authors conclude:

"Given the apparent inter-individual variation in efficacy and adverse effects of beta-blockers for prevention of perioperative MI, the biologic plausibility, and the low costs of genotyping by modern methods, it seems to us that a rigorous pharmacogenomic investigation is indicated. Ultimately, this could lead to a “genetic scorecard” that would recommend when a beta-blocker should be used and the dose, for prevention of perioperative MI."

As for me, I'm actually fine. I don't know what CYP2D6 alleles I carry, but the days full of adrenaline and jumping nerves are over. So, hooray for the beta-blockers!

[1] Nagele P, & Liggett SB (2011). Genetic Variation, β-blockers, and Perioperative Myocardial Infarction. Anesthesiology, 115 (6), 1316-27 PMID: 21918425

Photo: crystal sculpture, Santa Fe, NM. Canon 40D, focal length 85mm, shutter speed 1/30.