Friday, February 12, 2016

Heartbreaking drugs: A Valentine's Day special

Hey, it's a holiday-themed post!

Let's talk about hearts and how they get broken. Literally, with drugs.

When we swallow a pill, it's often to help address a problem we're experiencing with a particular body part. An aching head or a sore throat, for example. The pill breaks down in our guts and we absorb the drug into our bloodstream. It travels around our body and eventually ends up at the hurting locale where it works to fix the problem. Unfortunately, sometimes the drug will end up somewhere else and act there to cause an unwanted side effect. So while you can ingest a gel capsule filled with ibuprofen in order to have it travel to your head and relieve a headache, if you take any of about a zillion other drugs to fix a non-head-related issue you risk the drug causing a headache as a side effect. No body part is safe from the collateral damage inflicted by medicines. A particularly weird example I can think of is Cipro and other fluoroquinolones (used to treat bacterial infections), which on rare occasions can cause your Achilles tendon to tear in half.


Some drugs have cardiotoxic (heart-hurting) side effects. Obviously this is a big deal, since a properly functioning heart is somewhat essential to carrying on being alive. Using drugs known to be toxic to the heart is an exercise in risk assessment. If the side effect is super rare or the drug is super necessary for treating a life-threatening disease, it's likely to be deemed to be worth taking. I mean, penicillin and Tylenol will, on incredibly rare occasions, cause your skin to melt off (Google yourself some Stevens-Johnson syndrome if you dare), but they remain in widespread use. Sometimes a heart-wreaking side effect doesn't make itself apparent until after the drug reaches the market, at which point a swift withdrawal tends to take place.

Let's take a brief closer look at some heartbreakers.

Anthracyclines are a group of drugs used to treat cancers of the blood and various other tissues. They bind to an enzyme called topoisomerase-II in cancer cells, disrupting the transcription and replication of DNA, and thus preventing cells from multiplying. They also bind directly to DNA to accomplish the same task. The big problem with using anthracyclines is while they are great at killing cancer cells, they also damage non-cancerous heart cells (by inhibiting their topoisomerase-II, which appears to be particularly susceptible to the drugs). This eventually brings about ventricular dysfunction and heart failure, which sucks. The risk of heart failure is directly dependent on how much of the drug a person is given over the course of their chemotherapy, so oncologists watch things very carefully. The first of the anthracyclines to be discovered was daunorubicin, isolated from Streptomyces peucetius, a ruby red bacterium growing in soil near a 13th-century castle in southeast Italy. After this drug proved to be unreasonably toxic to people's hearts, researchers intentionally mutated S. peucetius and managed to coax it into producing a similar, slightly less cardiotoxic compound they named doxorubicin. Derivatives of the first two anthracyclines include epirubicin and mitoxantrone. Even with these engineered drugs, heart damage remains a concern.

A huge number of drugs are capable of breaking your heart by disrupting its electrical conduction system, which coordinates the sequential contraction of the four heart chambers to ensure maximum blood-moving efficiency. Shorting out the heart, so to speak, can result in torsades de pointes, an abnormal heartbeat that can sometimes lead to sudden death. Drugs known to mess with the heart's wiring include certain antiarrhythmics (e.g. amiodarone), antimicrobials (e.g. erythromycin), antipsychotics, and antihistamines.

A couple of drugs once used to promote weight loss (e.g. fenfluramine) or treat migraines (e.g. methysergide) can cause valvular heart disease. They accomplish their beneficial tasks by acting on serotonin receptors in the brain. However, they also appear to be able to affect receptors found in the valves of the heart, bringing about the development of structural abnormalities. The abnormal valves can leak (regurgitation), lowering the overall effectiveness of the heart. Symptoms of drug-induced valve disease can resemble those associated with heart murmurs or heart failure.

Finally, some drugs just straight up increase your risk of having a heart attack (also known as a myocardial infarction). These include oral contraceptives (aka "the pill") and certain non-steroidal anti-inflammatory drugs designed to specifically inhibit an inflammation-driving enzyme called COX-2 (e.g celecoxib).


References

Roden DM. 2008. Cellular basis of drug-induced torsades de pointes. British Journal of Pharmacology 154(7):1502-1507. [Full text]

Wu AH. 2008. Cardiotoxic drugs: Clinical monitoring and decision making. Heart 94(11):1503-1509. [Snippet]

Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, Yeh ET. 2012. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nature Medicine 18(11):1639-1642.

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