drug reactions Archives - Hormones Matter

Thinking About Side Effects

Published on September 29, 2022

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I have been thinking a lot about how we characterize the side effects of drugs. Truth be told, that is a topic that I have pondered on a number of occasions since beginning this website. More often than not, we have no idea about the true breadth and depth of these reactions. We think we do, because assuming some semblance of understanding, even an incomplete one, is what allows us to operate in this space, but when we unpeel the layers of that supposed understanding, it is difficult not to be impressed by how little we actually know.

The manufacturers of these products are required to report adverse reactions and side effects before a drug reaches the market and surveil reactions in the broader population after it reaches the market. From here, regulatory agencies, physicians, researchers, and consumers are expected to trust that we know how these drugs do or do not work. Importantly, we are encouraged by this understanding that any negative reactions experienced will be rare, time-limited, and easily mitigated by other medical products. The possibility that there might be side effects not identified by the original research, that ‘rareness’ is relative, and that ill-effects may not be time-limited or easily corrected is difficult to digest. It throws a wrench in the very foundation of the heavily fortified trust in all things modern medicine.

In reality, it is very difficult to ascertain the scope and depth of potential side effects. This is due in part to the complexity of the interactions between the drug, the human, and the totality of his/her environmental exposures and stressors and in part to the economic underpinnings of these endeavors. If one had to include a broader array of variables in a drug trial, no drug would ever be approved, at least not in a timely or cost-efficient manner. Instead, the initial trials utilize the most healthy of participants, perhaps excluding the disease process in question, and all other variables are excluded, both from the subject pool itself and analytically. Who wants to trial a drug on individuals typical of those who would be taking the drug; on individuals with multiple, often chronic comorbidities, for whom both chronic and acute polypharmacy are the norm and not the exception? No one. That would unfavorably skew the data. Better to have a clean subject pool and limit a priori what might be considered an adverse reaction to those that fall within the typically narrow anaphylactic framework and those that are directly related to the purported mechanisms of action of the drug itself. Addressing potential off-target effects must be eliminated or minimized; ditto for potential interactions between the drug and the unique characteristics of the individual. A clean sample and favorable data are the goal.

To that end, adverse reactions research, analyses, and reporting become a ‘see no evil’ approach. If we do not acknowledge the possibility that these reactions exist, then for all intents and purposes, they do not. This means that only the most severe and ‘on-target’ or anaphylactic reactions may be recognized. Any off-target reactions or side effects are labeled as rare and attributed to extraneous variables, unrelated to the drug but entirely related to some inherent weakness of the human who takes the drug.

If confronted with the prospect of negative reactions or even simply negative data e.g. the drug does not work, it is incumbent upon those involved to utilize analytical tools that highlight the good and hide the bad. Data or participant responses that do not fit the desired narrative must be cleaned or removed, post hoc. When that does not work, it is common to select complex statistical methods that no one but the statisticians themselves understand to obfuscate negative findings. Inasmuch as few physicians and even fewer consumers understand even the most basic statistics, this all but eliminates any questions regarding the veracity of the findings. What is written in the abstract or summary is all that will matter. The lede is buried in the stats so that everyone involved might trust in the medication’s safety, trust in their own knowledge, and move comfortably along with their lives.

I admit, this is a cynical perspective, but it is hard-won. After a decade of publishing HM, researching the analytical methodologies employed by drug companies, of investigating the mechanisms of action of many popular and presumed safe drugs, it is difficult not to be jaded. So flimsy are the safety and efficacy data that one is hard-pressed not to question everything. And so here I am amidst a global pandemic for which multiple products have been rushed to market. Pressure to use these products is intense and I and others are left with the sinking feeling that we do not yet know what we think we know about these products or even what we do not know. What we do know is that the developers and manufacturers of these products have a long and well-established history of shady research practices, of burying negative data, of vilifying anyone who questions these practices, and of financing unquestioning support from politicians, ‘thought leaders’, media, and generally, anyone who might be of use. It is not difficult to recognize those same practices at play here but the desire to be safe quells those concerns for most. We’ll take anything and do anything to end this mess, except perhaps ask why we are here in the first place.

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This article was published originally on November 4, 2021.

Common Drugs Trigger Heart Rhythm Irregularities

by Lisa Bloomquist

Published on May 24, 2017

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According to the Mayo Clinic web site, “More than 50 medications, many of them common, can lengthen the QT interval in otherwise healthy people and cause a form of acquired long QT syndrome known as drug-induced long QT syndrome. Medications that can lengthen the QT interval and upset heart rhythm include certain antibiotics, antidepressants, antihistamines, diuretics, heart medications, cholesterol-lowering drugs, diabetes medications, as well as some antifungal and antipsychotic drugs.”

A layman’s description of the QT interval is also found on the Mayo Clinic web site, “After each heartbeat, your heart’s electrical system recharges itself in preparation for the next heartbeat. This process is known as repolarization. In long QT syndrome, your heart muscle takes longer than normal to recharge between beats. This electrical disturbance, which often can be seen on an electrocardiogram (ECG), is called a prolonged Q-T interval.”

A prolonged QT interval is significant because, “The prolongation of QT interval is a risk factor for sudden cardiac death independent of the patient’s age, history of myocardial infarction, heart rate, and history of drug use; the patients with a QTc interval of >440 milliseconds are at 2 to 3 times higher risk for sudden cardiac death than those with a QTc interval of <440 milliseconds. The mortality rate in untreated patients with LQT is in the range of 1% to 2% per year” (emphasis added).

Many common medications, including heart medications and cholesterol-lowering drugs (oh, the irony), can cause serious heart rhythm irregularities that can lead to death.

Drugs that lengthen the QT interval include tricyclic antidepressants, fluoxetine/Prozac, Haldol, macrolide antibiotics (azithromycin being the most popular), fluoroquinolone antibiotics (Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin and a few others), and others. A complete list of drugs that cause elongated QT can be found at www.qtdrugs.org.

These drugs worsen the elongation of the QT interval in a dose-dependent manner, so drugs that are known to lengthen the QT interval should not be taken concurrently. Additionally, drugs and foods that interfere with the CYP450 enzymatic pathways, which are necessary for drug metabolism, may cause a build-up of QT elongating drugs in the body. Drugs and foods that inhibit CYP450 enzymes should not be taken with QT interval elongating drugs.

To put this into real-world terms, if you’re on Prozac, you should avoid (or at least exercise caution with) azithromycin. If you’re on Amiodarone (a heart medication), you should avoid (or at least exercise caution with) fluoroquinolone antibiotics. When you’re on any drug that elongates the QT interval you shouldn’t drink grapefruit juice because it interferes with CYP450 enzymes.

Antibiotics that Elongate the QT Interval

In March, 2013, the FDA announced that they were, “warning the public that azithromycin (Zithromax or Zmax) can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm. Patients at particular risk for developing this condition include those with known risk factors such as existing QT interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or use of certain drugs used to treat abnormal heart rhythms, or arrhythmias.” The warning label for azithromycin was adjusted accordingly. Whether or not enough attention was paid to the updated warning label to change prescribing habits, or whether or not the updated warning label resulted in prevention of any irregular heart rhythm related deaths, are unknown.

The FDA announcement of the warning label changes for azithromycin noted that, “The risks of cardiovascular death associated with levofloxacin treatment were similar to those associated with azithromycin treatment.”

The warning label for Levaquin/levofloxacin (and the other fluoroquinolone antibiotics) notes that:

“Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval.”

In 2014, a study entitled “Azithromycin and Levofloxacin Use and Increased Risk of Cardiac Arrhythmia and Death” compared the risk of cardiac arrhythmia for U.S. Veterans taking amoxicillin, azithromycin and levofloxacin. The study concluded that:

“Compared with amoxicillin, azithromycin resulted in a statistically significant increase in mortality and arrhythmia risks on days 1 to 5, but not 6 to 10. Levofloxacin, which was predominantly dispensed for a minimum of 10 days, resulted in an increased risk throughout the 10-day period.”

Yes, azithromycin can increase the risk of serious cardiac events in those who take it, but levofloxacin is more dangerous, with an increase in serious cardiac events occurring for ten days, as opposed to five with azithromycin. Longer term tests – comparing health outcomes for those who took various kinds of antibiotics months or years after administration of the drugs – were not conducted. There seems to be an assumption that drugs are only dangerous while they are being administered. As a consequence, long-term adverse effects are systematically under-studied.

Many patients who have experienced fluoroquinolone toxicity syndrome have reported heart rhythm abnormalities long after they have stopped taking fluoroquinolone antibiotics. Whether or not past use of fluoroquinolones makes people more subject to long QT syndrome, torsades de pointes or other potentially fatal heart rhythm irregularities over their lifetime, has not, to my knowledge, been examined. What has been examined is that both azithromycin and levofloxacin increase the risk of heart rhythm abnormalities significantly while taking them. Even that information is enough to warrant caution with both drugs.

Treatment for Medication-Induced Heart Rhythm Irregularities

For the treatment of long QT syndrome, it is recommended that the offending medication be ceased. Please note, one should not stop a medication without physician assistance. For acute QT attacks, IV magnesium and potassium may be necessary. “Magnesium is very effective for suppression of the short-term recurrences of torsades and is the agent of choice for the immediate treatment of the torsades associated with both congenital and acquired forms of LQT, irrespective of serum magnesium levels.” Additionally, “Administration of potassium is considered an important adjunct to the intravenous magnesium therapy for the short-term prevention of the torsades, especially in the cases where the serum potassium level is in the lower limits.” A pacemaker is a longer-term treatment option for those whose condition demands one.

The cases of long QT syndrome that are caused by drugs can be avoided entirely by avoiding the drugs that elongate the QT interval. Of course, don’t go off any medication without first consulting your doctor. I am not a doctor, so this post should not be interpreted as medical advice. I know that given my past adverse reaction to a fluoroquinolone antibiotic (ciprofloxacin), I will do my best to avoid the drugs listed on www.qtdrugs.org. Your heart may thank you if you do the same.