Which antihypertensive medication is most likely to cause dose‑related peripheral edema: lisinopril, losartan, hydrochlorothiazide, amitriptyline, or metoprolol?

None of the Listed Medications Are Calcium Channel Blockers—The Question Contains a Fundamental Error

Among the five drugs listed, none is a dihydropyridine calcium channel blocker, which is the antihypertensive class most strongly associated with dose-related peripheral edema. However, if forced to choose from this list, amitriptyline (a tricyclic antidepressant, not a true antihypertensive) would be the answer by exclusion, though it causes edema through entirely different mechanisms than vasodilatory edema.

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Why This Question Is Problematic

• Lisinopril (ACE inhibitor), losartan (ARB), hydrochlorothiazide (thiazide diuretic), and metoprolol (beta-blocker) are not associated with dose-dependent peripheral edema as a primary adverse effect. 1, 2

• Amitriptyline is a tricyclic antidepressant occasionally used off-label for resistant hypertension but is not a guideline-recommended antihypertensive agent; it can cause fluid retention through anticholinergic and antihistaminic effects, not through the vasodilatory mechanism seen with calcium channel blockers. 3

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The Correct Answer to the Intended Question

Dihydropyridine Calcium Channel Blockers Cause Dose-Related Peripheral Edema

• Dihydropyridine calcium channel blockers (amlodipine, nifedipine, felodipine) are the antihypertensive class most likely to cause dose-dependent peripheral edema, with incidence ranging from 5% at low doses to 30% at maximum doses. 2, 4

• The mechanism is selective precapillary arteriolar vasodilation without venous dilation, which increases intracapillary hydrostatic pressure and drives fluid extravasation into the interstitium. 3, 2

• This edema is gravitational (worse in dependent limbs), non-pitting initially, and does not respond to diuretics because it is not due to sodium retention. 2, 4

• Women experience peripheral edema from calcium channel blockers more frequently than men, with rates as high as 50% in some studies. 1

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Why the Listed Drugs Do NOT Cause Dose-Related Peripheral Edema

Lisinopril (ACE Inhibitor)

• ACE inhibitors cause angioedema (a life-threatening allergic reaction affecting the face, lips, tongue, and larynx) in 0.1–0.7% of patients, but this is not dose-related peripheral edema. 5

• Lisinopril does not cause dependent leg swelling through vasodilatory mechanisms. 4

Losartan (Angiotensin Receptor Blocker)

• ARBs like losartan do not cause peripheral edema as a primary adverse effect. 6

• In fact, adding losartan to amlodipine reduces calcium-channel-blocker-induced edema by restoring venous tone and reducing intracapillary pressure. 2, 4

Hydrochlorothiazide (Thiazide Diuretic)

• Thiazide diuretics reduce extracellular fluid volume and are used to treat edema, not cause it. 7

• Rare case reports describe acute non-cardiogenic pulmonary edema from hydrochlorothiazide hypersensitivity (an allergic reaction), but this is not dose-related peripheral edema. 8

Metoprolol (Beta-Blocker)

• Beta-blockers do not cause peripheral edema through vasodilatory mechanisms. 1

• In heart failure, beta-blockers may transiently worsen fluid retention during initiation, but this is a hemodynamic effect in decompensated patients, not a drug-specific adverse effect in hypertension. 1

Amitriptyline (Tricyclic Antidepressant)

• Amitriptyline can cause weight gain and fluid retention through anticholinergic effects (reduced sweating, urinary retention) and antihistaminic effects (increased appetite), but this is not the dose-dependent vasodilatory edema seen with calcium channel blockers. 3

• It is not a guideline-recommended antihypertensive and should not appear in a list of standard antihypertensive agents.

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Clinical Pearls: Managing Calcium-Channel-Blocker-Induced Edema

First-Line Strategy: Add an ACE Inhibitor or ARB

• Adding an ACE inhibitor (e.g., lisinopril 10–20 mg) or ARB (e.g., losartan 50–100 mg) to a dihydropyridine calcium channel blocker reduces edema by 50–70% by restoring postural venous vasoconstriction and lowering intracapillary pressure. 2, 4

• This combination is more effective than adding a diuretic, which does not address the underlying vasodilatory mechanism. 2

Second-Line Strategy: Switch to a Non-Dihydropyridine Calcium Channel Blocker

• Diltiazem and verapamil (non-dihydropyridines) cause significantly less peripheral edema than amlodipine or nifedipine because they dilate both arterioles and veins, maintaining capillary pressure balance. 2

Third-Line Strategy: Switch to a Different Dihydropyridine

• Lercanidipine and lacidipine cause less edema than amlodipine or nifedipine at equivalent antihypertensive doses. 2

What Does NOT Work

• Diuretics are ineffective for calcium-channel-blocker-induced edema because the fluid is in the interstitium, not the intravascular space. 2, 4

• Compression stockings provide symptomatic relief but do not address the underlying mechanism.

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Common Pitfall: Misattributing Edema to Heart Failure

• Patients on calcium channel blockers who develop peripheral edema are often incorrectly diagnosed with heart failure and started on diuretics, which are ineffective and delay appropriate management. 2

• Always consider drug-induced edema first in patients on dihydropyridine calcium channel blockers before pursuing extensive cardiac workup.