For Clinicians | Drug Interactions in a Disaster: The Combinations a Bad Week Creates

By Dr. Jamie Wilkey, PharmD, Director of Clinical Education
Medically reviewed and edited by Kristen Carpenter, PA-C

When we think about prescription medicine in a disaster, we most often think about supply. Does the patient have enough of what they’re already taking? Can we get them something for the wound or the infection that happened because of the disaster?

I’m a pharmacist, so I also think about another way that disasters mess with our medications and that is drug interactions. Drug interactions are what happens when one thing changes what another thing does inside the body. Two prescriptions can do it. So can a prescription and something off a shelf, an ibuprofen, an antihistamine, a supplement nobody thinks to mention. And so can a prescription and the shape the patient is in, which is the version a disaster is good at making. Most of the year a computer catches these. In a disaster people take more medication and newer medication with less prescriber and pharmacist oversight, because we aren’t as easily reached.

Adverse drug events send about 4 of every 1,000 Americans to an emergency department each year, and the top two classes are anticoagulants and antibiotics.¹ A disaster does three things at once. It puts new drugs in people’s hands. It also can lead to dehydration. And lastly, it takes away convenient lab work. Today I’ll walk through the three dangerous drug interaction combinations that can result from a disaster, a few smaller traps, and how to keep an eye out for your patients ahead of time. 

Few New Medications

It’s easy to picture a disaster putting everybody on a pile of new medication. That isn’t what happens. Most people are taking what they were taking a week ago. A smaller group picks up something new, and it lands in three classes: an antibiotic, an NSAID, and an antihistamine.

As far as medications go those drug classes are generally basic and largely benign. What I want to talk with you about is that these are three drug classes you’d hand someone without a second thought because two of them produce all three of the cases below. Ordinary is what makes them dangerous, because nobody stops to check an ordinary drug.

The antihistamine is the odd duck here, because it doesn’t need a collision with another drug or new health condition to cause a problem. Diphenhydramine sits on the Beers list as highly anticholinergic, and clearance falls with age, so confusion, dry mouth and constipation all get more likely in an older patient, and cumulative anticholinergic exposure carries its own risk of falls and delirium.² Beers still says it may be appropriate for acute treatment of a severe allergic reaction, which is the disaster presentation, so here is a tricky medication that should be used in an emergency, but also watched very carefully for anyone over 65 years old.

 The Kidney Triple Whammy from Dehydration

A patient on a diuretic and an ACE inhibitor or ARB has been fine on that combination for years. Then comes three days of hauling debris in the heat, less water than they should be drinking, maybe some diarrhea. Their back hurts, so they take an ibuprofen.

Those three together have a name, the triple whammy, and the kidney is what gets walloped. A kidney filters by holding pressure across the filter, and when blood volume drops it protects that pressure two ways: it widens the vessel coming in and tightens the one going out. The NSAID blocks the widening. The ACE inhibitor or ARB blocks the tightening. Both of the kidney’s own defenses are gone at the same moment the diuretic and the dehydration are sending it less blood to work with. A 2025 meta-analysis of four studies and 42,367 patients put the odds of acute kidney injury at about double, OR 2.01 (95% CI 1.30 to 3.10).³ One study inside that review found the three-drug combination carried 1.64 times the risk of the two-drug version,³ so the ibuprofen really is what tips the scales here.

Nothing about their prescription changed. The dehydration and the extra NSAID broke a smooth-running system. 

Warfarin Plus an Antibiotic, With No Lab Draw

The second case here is the same story, but mixing it up with a different organ. This interaction will surprise nobody because it is warfarin–the medication that is ultra sensitive and seems to interact with everything. Warfarin plus a handful of common antibiotics pushes the INR up, partly because the antibiotic slows the enzyme that clears warfarin, partly because it kills off the gut bacteria that make vitamin K. The high-risk list is pretty short: TMP-SMX, ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin and clarithromycin.⁴

Disasters make blood draws a lot harder to get and they aren’t particularly top of mind in an event like that. In a cohort of 22,272 warfarin patients, TMP-SMX carried a hazard ratio of 2.09 for serious bleeding and ciprofloxacin 1.87, and 9.7% of the patients given fluconazole ended up with an INR above 6.⁴ Then the part that matters for a storm: patients who got an INR within 3 to 14 days of starting the antibiotic had a lower risk of serious bleeding, HR 0.61 (95% CI 0.42 to 0.88).⁴

The interaction was always there. The lab is what disappeared in a disaster.

Bactrim +  Spironolactone

This third and final big interaction is kind of the opposite because nobody expects it. Bactrim for a UTI, in a patient on spironolactone for heart failure, and both drugs are holding onto potassium like it is going out of style. Trimethoprim blocks the same channel in the kidney that amiloride does, so it behaves like a potassium-sparing diuretic stacked on top of the one the patient is already taking.

In a population study of Ontario patients 66 and older who were taking spironolactone, sudden death within 14 days of an antibiotic prescription was more than twice as likely with TMP-SMX as with amoxicillin, adjusted OR 2.46 (95% CI 1.55 to 3.90).⁵ Ciprofloxacin came in elevated too, at 1.55.

Here’s why it belongs in a disaster article. This is the combination you’d normally check a potassium on, and in a really bad week nobody is checking anything. The good news is that the fix is so easy: just picking a different antibiotic. Amoxicillin is the drug everything else in that study was measured against.

A Few Smaller Traps

These don’t each need their own section, but they come up every time.

• Know the acetaminophen ceiling. FDA’s over-the-counter limit is 4,000 mg in 24 hours for adults,⁶ Tylenol’s own Extra Strength label lowered it to 3,000, and the label warns separately about 3 or more alcoholic drinks a day.⁷ Prescription combination products have been capped at 325 mg per unit since 2014, but over-the-counter cold, flu and sleep products never were, which is how somebody stacks two products and blows past the ceiling without exceeding a single label.⁶
• Know which way to swap between ibuprofen and acetaminophen. For the patient who is dehydrated, on a diuretic with an ACE inhibitor or ARB, or on warfarin, acetaminophen is the safer analgesic. Use ibuprofen when the liver is the bigger worry: heavy alcohol use, liver disease, or a patient already getting acetaminophen from a combination product.
• Don’t let thirst be the cue. CDC lists diuretics, ACE inhibitors and ARBs as reducing thirst sensation, so the patients who most need to drink are the least likely to feel like it.⁸ Tell them to drink on a clock whether they feel thirsty or not.
• Watch what may bind with the antibiotic. Antacids, calcium and iron cut absorption of both doxycycline and the fluoroquinolones,⁹ and bismuth subsalicylate, the Pepto in the cabinet, is on doxycycline’s list too.¹⁰
• Address the sun! Doxycycline causes an exaggerated sunburn reaction and the and the fluoroquinolones carry their own photosensitivity warning.⁹ The doxycycline label says to stop the doxycycline at the first sign of skin redness,¹⁰ which is a hard instruction in a week with nothing else on the shelf, so make sure they know to cover up and stay out of direct sun for the whole course.

Where This Fits

We want everyone looking at the whole picture of a patient’s medications in a disaster. We’re a team of pharmacists, physicians and PAs, and we catch these same interactions in ordinary clinic weeks: the ibuprofen on top of the ACE inhibitor, the Bactrim in the spironolactone patient. The chemistry doesn’t change in a disaster. What changes is that the catching stops. The screen, the lab and the pharmacist who would have caught it all get harder to reach in an emergency.

So, Jase does the clinical work early. A licensed provider reviews the request and writes the prescription ahead of time, for a short list of predictable problems, for emergency use only and after the patient has tried to reach a qualified provider. That’s what we mean by appropriate medical preparation. We also mean helping patients know, before a disaster, which items on their own medication list are most likely to cause trouble.

The drugs a disaster adds are boring. What makes them dangerous is the patient’s existing medication list. 

Sources

1. Shehab N, Lovegrove MC, Geller AI, Rose KO, Weidle NJ, Budnitz DS. US emergency department visits for outpatient adverse drug events, 2013-2014. JAMA. 2016;316(20):2115-2125. https://pmc.ncbi.nlm.nih.gov/articles/PMC6490178/
2. 2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081. https://doi.org/10.1111/jgs.18372
3. Calvo DM, Saiz LC, Leache L, Celaya MC, Gutiérrez-Valencia M. Acute kidney injury and morbi-mortality associated with “triple whammy” combination: systematic review and meta-analysis. Br J Clin Pharmacol. 2025;91(11):3031-3041. https://pmc.ncbi.nlm.nih.gov/articles/PMC12569550/
4. Lane MA, Zeringue A, McDonald JR. Serious bleeding events due to warfarin and antibiotic co-prescription in a cohort of veterans. Am J Med. 2014;127(7):657-663.e2. https://pmc.ncbi.nlm.nih.gov/articles/PMC4116816/
5. Antoniou T, Hollands S, Macdonald EM, Gomes T, Mamdani MM, Juurlink DN. Trimethoprim-sulfamethoxazole and risk of sudden death among patients taking spironolactone. CMAJ. 2015;187(4):E138-E143. https://pmc.ncbi.nlm.nih.gov/articles/PMC4347789/
6. US Food and Drug Administration. Acetaminophen. Safe Use of Over-the-Counter Pain Relievers and Fever Reducers. https://www.fda.gov/drugs/safe-use-over-counter-pain-relievers-and-fever-reducers/acetaminophen
7. Tylenol Extra Strength (acetaminophen) Drug Facts label. DailyMed, US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=59773893-09a8-47a2-943a-e9ea9da4458a
8. Centers for Disease Control and Prevention. Heat and Medications: Guidance for Clinicians. https://www.cdc.gov/heat-health/hcp/clinical-guidance/heat-and-medications-guidance-for-clinicians.html
9. CIPRO (ciprofloxacin hydrochloride) tablets, prescribing information. US Food and Drug Administration, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/019537s095,020780s050lbl.pdf
10. Doxycycline hyclate tablets and capsules, prescribing information. DailyMed, US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fad03768-f1d2-459f-965e-0ec29f189f1f