Medicine For People!

May 2017: Drug Side Effects

By Ralf Roletschek - Own work, CC BY-SA 3.0, Link

Drug Side Effects

Anything Can Cause Anything

A young general practitioner, I sat in the physician's workroom at Elmbrook Hospital in Brookfield, Wisconsin, writing up a record on a patient who wasn't doing well. When the internist came in and sat next to me, I expressed my frustration that the furosemide I had given the patient to remove the fluid from his lungs had caused edema of the legs.

"How can that happen? That's the opposite of what it should do. Plus, edema is not on any list of side effects for furosemide."

Without looking up, and with a sigh of commiseration, the internist replied, "anything can cause anything."

So, when patients ask me, upon receiving a prescription for a new drug, "what are the side effects?", that's what I want to say.

Let me take as an example a commonly prescribed drug for high blood pressure, ramipril (you may know it under the brand name Altace). Lisinopril, which is in the same drug class, is more popular, but people on ramipril seem to live longer. The side effects are generally similar for both.

Federal Food and Drug Administration Label

No pharmaceutical hits the US market without a label. This is a legal as well as a medical document, and certainly (behind the scenes) a source of hot contention between the pharmaceutical company and the FDA. That said, a lot of work and thought goes into these and they always merit informed reading.

You can see all the adverse effects for ramipril listed in the FDA package insert. The FDA has even included a helpful summary of major points about this drug on page 1 of the 19-page prescribing information. This says that the most common side effects are headache, dizziness, fatigue, and cough. When you look at the more detailed information on pages 7 and 8, however, you see no mention of headache or fatigue. What you do see is the real issue, which is that cough occurs 2 to 3 times more frequently with ramipril than it does with a placebo. Every physician knows this. We prescribe this class of drugs frequently; about 1 in every 12 to 15 people will have a noticeable cough as a result, and we hear about this.

Adverse Effects

Compare this with the 1 in 25 people who are going to experience dizziness; so will about 1 in 25 given a sugar pill. Not so interesting, no? (This is stated on page 8 of the insert if you want to see it).

Headache and fatigue? Both of those are on the FDA short list, but every doctor knows that, like dizziness, headache and fatigue are going to be on the side effect list for about every pharmaceutical in the book, and most likely the likelihood of those side effects will be no greater with the drug than it will be with a placebo.

Compare with Placebo

This table illustrates the numbers attached to the side effects judged to be most important. (No headache and fatigue. Go figure.)

Table of Important Side Effects

Source: , page 8.

Some of these adverse effects appear to be much the same between ramipril and placebo; the table heading says as much, with its "adverse events possibly/probably related."

Expected Adverse Effects

If you take a pharmaceutical to lower blood pressure, it's no surprise that it sometimes lowers it too much (hypotension), that it can cause a brief period of low blood pressure on standing (postural hypotension), that a person might faint because of this (syncope is the doctor's fancy word for fainting), and that they might develop a sense of spinning (vertigo), or dizziness. In other words, about half of these adverse events mean the drug is doing what it's supposed to.

Many of the people receiving this drug have heart disease and kidney malfunction as well. So the slight increase of angina pectoris and worse kidney function in people taking the drug versus those taking placebo rates as "possibly/probably related." Long story, actually, but to be precise in most cases we just don't know. And if you are well enough to be sitting in the average primary care doc's office asking questions, this doesn't apply to you.

This leaves nausea, vomiting, and diarrhea, adverse effects you find on the list for just about any pharmaceutical in the book, and prime examples of the "anything can cause anything" rule.

This is why, when you ask your physician what the adverse effects of a drug in this class are, most likely you're going to be spared the "possibly/probably" spiel and told "if anything, it might cause a cough. If it does, come back and we will switch you to something that doesn't do that."

Now, a wiseacre in the class might object, saying "why not prescribe the ‘something that doesn't do that' in the first place?" If you wonder this, your homework is to look up the FDA list of possible/probable side effects of all the other drugs prescribed for high blood pressure.

Black Box Warnings

Read all the fine print in the FDA label referenced above, and you'll see a number of really terrible adverse events. Whether these are truly related to ramipril or not, not even the FDA really knows; most likely no one is actively working to find out. Millions of people take these types of drugs, and as happens in all groups of people, both terrible and minor illnesses and conditions regularly occur.

When the FDA thinks there is a real risk of a medication causing an unusual and serious side effect, they put the warning in what we call a "black box." Here's the one for ramipril.

FDA warning for Ramipril


Department of Duh!

You don't have to be a medical professional to figure out that stimulants can cause insomnia, high blood pressure drugs can cause low blood pressure, diabetes drugs can cause low blood sugar, or sleeping pills can cause falls at night. In lawsuit-happy America, such risks are listed a zillion times in every printed resource for every doctor and patient.

Real Adverse Effects

But sometimes we have to choose between no treatment and treatment with guaranteed side effects. This is especially true of cancer treatment: people will put up with hair loss, vomiting, and other more serious problems when the goal is to be free of cancer.

If you need short-term corticosteroids (prednisone or its many sister drugs collectively known as steroids) to fight a serious case of inflammation, you'll probably be told that the side effect list is not only long but much more certain. People on long-term, high-dose steroids really do have a much higher risk of elevated blood pressure, elevated blood sugar, ulcers, bruising, changes in facial appearance, infection, and more problems.

Fortunately, most of the time we can get away with a few days or weeks of treatment before serious side effects have time to develop.

The Real Risks of Pain Relief

Acetaminophen (Tylenol is the common brand name) can wreck the liver irretrievably, especially when used with alcohol. NSAIDS such as ibuprofen (Advil) and naproxen (Aleve) rarely harm the liver; I've never seen it happen. But they can trash the kidneys, especially when people are dehydrated. How many of you have read the package insert that came with your over-the-counter pain reliever?


You've heard over and over with just about any medicine you've been given to call your doctor right away if you develop a rash, itching, or trouble swallowing. These are not side effects. They are signs that you are allergic to the drug. Allergy is a different kind of "adverse effect" and can sometimes require prompt treatment.

The Future of Side Effects?

Genetic testing will allow us to avoid giving certain drugs to people whose metabolic make-up pretty much assures they'll have an adverse response. RIght now such testing is costly and not widely available. But it's coming!

Thanks to Jody Bower for editorial improvements.



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Medicine for People! is published by Douwe Rienstra, MD at Port Townsend, Washington.