Top 5 OTC Drug Interactions

Over-the-counter medications provide easy access for patients to solve their own problems. Too often, patients lean on self-treatment without consulting a healthcare professional. One of my primary concerns with this is unforeseen drug interactions. I’ll break down my top 5 OTC drug interactions.


NSAIDs make the top of the list when it comes to OTC drug interactions. Ibuprofen and naproxen are used with frequent regularity by patients. Geriatric patients are particularly at risk for complications due to drug interactions and adverse effects. NSAIDs can increase bleeding risks and this will be exacerbated by patients who are taking antiplatelet or anticoagulant medications. NSAIDs may also contribute to other cardiovascular concerns such as hypertension (oppose blood pressure lowering medications) and CHF (oppose benefits of loop diuretics). Renal impairment is also a concern and NSAIDs can have an additive risk when using them with diuretics, ACE inhibitors, ARBx, or an ARNI. The other most relevant drug interaction involves our patients with bipolar patients who are taking lithium. Concentrations of lithium (case study) can rise when used in combination with NSAIDs.


Most notably, calcium can have drug interactions with tetracycline and quinolone antibiotics. In practice, I still see a fair amount of use of doxycycline, ciprofloxacin and levofloxacin. When combined with these medications, calcium essentially binds up the drug and blocks absorption. This can lead to inadequate concentrations and ultimately treatment failure. Other medications that also may be affected by this type of binding interaction include levothyroxine, bisphosphonates, baloxavir, and certain HIV medications.


Omeprazole is commonly used for GERD symptoms and can be a source for OTC drug interactions. Citalopram and clopidogrel are two of the most infamous interactions. Citalopram concentrations can increase on account of CYP2C19 inhibition while clopidogrel (Podcast) action may be blunted. The clopidogrel interaction is a bit more controversial but I think it should at a minimum be reviewed.


Many of the older antihistamines such as diphenhydramine and doxylamine are highly anticholinergic and sedating. They can certainly be responsible for many OTC drug interactions. Additive anticholinergic activity from medications like TCAs, antispasmodics, urinary anticholinergics, and others can increase the risk of confusion, dry eyes, dry mouth, urinary retention, and constipation.

CNS depression is also a concern with the 1st generation antihistamines. Additive effects from medications like benzodiazepines and opioids can lead to excessive sedation.


Last on my list of OTC drug interactions is pseudoephedrine. Pseudoephedrine can directly oppose the beneficial effects of antihypertensives due to its alpha agonist activity. The other notable interaction with pseudoephedrine is with BPH. The alpha-agonist activity can directly oppose the benefit of alpha-blockers and worsen symptoms of BPH.

If you’d like to hear me cover 2 hours of geriatrics, I am speaking live at an upcoming conference and I will cover these drug interactions as well as much more on polypharmacy and the prescribing cascade. It is a paid conference, but you can check out the jam-packed lineup here.


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Written By Eric Christianson

September 18, 2022

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