Drug Interactions: Top 5 High Alert Medications

By Guest Author Eric Christianson, PharmD, BCGP, BCPS

Drug interactions are everywhere. They are particularly everywhere if you have chosen to work in geriatrics. Determining clinical significance and risk mitigation is what is really challenging. I primarily practice as a clinical pharmacist in geriatrics and have pulled together a list of medications so that when you see them, you’ll be aware of the potential for drug interactions.  

I also wanted to create a list that wasn’t 20-30 meds to try to remember, because I certainly could have done that.  Without further ado, here are my top 5 medications that have a ton of drug interactions.


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Common medications used for infections like sulfamethoxazole/trimethoprim, metronidazole can substantially raise INR.  Many clinicians are well aware of these interactions when medications are started, but you also need to recognize the clinical impact of drug interactions when medications are discontinued.  In one scenario, I remember a patient on rifampin (a potent enzyme inducer) for 12 weeks.  The warfarin had to be increased by several milligrams per day to maintain a therapeutic level during treatment.  Following discontinuation of the rifampin, the INR skyrocketed to almost 10.  The team did not recognize that when the antibiotic course was complete, the warfarin dose would have to be adjusted back downward.


Fluconazole is a potent CYP3A4 inducer and often used for yeast and other fungal infections.  This medication can substantially raise concentrations of other medications that are also metabolized through 3A4.  Common medications that can be impacted by fluconazole include amiodarone, phenytoin (I’ve seen a case of toxicity due to this one), and warfarin. 


QTc prolongation interactions are everywhere with this medication.  Levofloxacin, antipsychotics, ondansetron, citalopram, and many other medications can potentially prolong the QT interval.  Reviewing an EKG prior to starting some of these medications would be advisable in a patient taking amiodarone.  Amiodarone also has substantial interactions with warfarin, digoxin, and statin type medications.  CYP3A4 drug interactions are also prevalent with amiodarone.


Phenytoin is an enzyme induce and can reduce concentrations of several different medications.  Apixaban, amiodarone, and some antipsychotics are just a few examples of how phenytoin could negatively impact previously therapeutic concentrations. Phenytoin is also notorious for chewing up vitamin D by inducing metabolism and reducing overall levels.  If you are looking for more pearls on phenytoin, check out this podcast episode.


While I would overall say that NSAIDs have fewer drug interactions than the other medications this list, the frequency of use and easy availability of NSAIDs can lead to substantial challenges with drug interactions.  Warfarin (blood thinners in general) and lithium are two clinically significant examples of interactions.  Another common interaction is the risk to the kidney when NSAIDs are combined with ACEI’s, ARBs, or diuretics.


Authored by: Eric Christianson, PharmD, BCGP, BCPS founder of the Real Life Pharmacology podcast and nationally recognized clinical pharmacy blog Meded101.com. He has been quoted in the Wall Street Journal, acknowledged by the American Journal of Nursing, Pharmacy Times, and Pharmacy Podcast. He has also authored several Amazon Best Selling books on medication related topics.


1 thought on “Drug Interactions: Top 5 High Alert Medications”

  1. An excellent quick review which is necessary for most clinicians including physicians. I appreciate the article and the younger age of the author.

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