Can any of these medications, including ubrogepant, ondansetron, sertraline, lisinopril, trazodone, and diazepam, cause swelling in the legs?

Lisinopril is the Most Likely Culprit for Leg Swelling

Among your medications, lisinopril is the most likely to cause leg swelling, though it does so through a mechanism (angioedema) that differs from typical peripheral edema. ACE inhibitors like lisinopril are well-documented to cause angioedema, which can manifest as swelling in the extremities 1. However, if the swelling is bilateral, symmetric, and pitting (typical peripheral edema), lisinopril is less likely the cause since ACE inhibitors don't typically cause this type of edema 2.

Medications in Your List and Their Edema Risk

High-Risk Medications

• Lisinopril (10 mg daily): ACE inhibitors cause angioedema as a class effect through bradykinin accumulation 1. This typically presents as facial or airway swelling but can affect extremities. The incidence is relatively low but serious when it occurs 1.

Low to Negligible Risk Medications

• Sertraline (50 mg daily): SSRIs are not recognized causes of peripheral edema in the medical literature 3, 4.

• Trazodone (75 mg at bedtime): Not a documented cause of peripheral edema 5, 4.

• Ondansetron (4-8 mg twice daily): Antiemetics are not associated with leg swelling 4.

• Ubrogepant (100 mg as needed): CGRP receptor antagonists for migraine are not known to cause peripheral edema 4.

• Diazepam (10 mg pre-procedure): Benzodiazepines do not cause peripheral edema 4.

Clinical Approach to Your Situation

Determine the Type of Swelling

• If the swelling is bilateral, symmetric, and pitting: This is typical peripheral edema, which is NOT commonly caused by any of your medications 3, 4. Consider other causes such as venous insufficiency, heart failure, or kidney disease 4.

• If the swelling is asymmetric, non-pitting, or associated with skin changes: Consider lisinopril-induced angioedema, especially if accompanied by facial swelling or difficulty breathing 1.

Management Algorithm

1. Immediate action if angioedema suspected: Discontinue lisinopril immediately and seek emergency care if there's any facial swelling, tongue swelling, or breathing difficulty 1.

2. For typical bilateral leg edema:

   • Lisinopril is unlikely the cause since ACE inhibitors don't cause sodium retention-type edema 2
   • Evaluate for cardiac, renal, or venous causes before attributing to medications 3, 4
   • Consider that none of your other medications are high-risk for peripheral edema 4

3. If lisinopril must be discontinued: Switch to an angiotensin receptor blocker (ARB) which has lower rates of angioedema, though cross-reactivity can occur 3.

Important Caveats

• Diuretics are not on your medication list: If leg swelling develops and lisinopril is discontinued, adding a diuretic may be necessary for symptomatic relief 3.

• The combination of multiple medications: While none of your other medications individually cause edema, polypharmacy can contribute to fluid retention through complex mechanisms 4.

• Timing matters: Drug-induced edema typically develops within weeks to months of starting or increasing a medication dose 6, 7. If your swelling is new and correlates with starting lisinopril, this strengthens the association 1.