The only medication contraindicated with lithium
- Jason Cafer MD
- 1 day ago
- 3 min read
Cafer's Psychopharmacology Second Edition Series: Prescribing Lithium paperback is now available!
Lithium and Lisinopril Interaction
Lisinopril increases lithium levels ~36% on average, similarly to other ACE inhibitors and ARBs under usual circumstances. Lisinopril is implicated in ~1/3 of lithium toxicity cases, largely because it the #2 most-prescribed medication in the U.S.
According to The Lithium Handbook (Meyer & Stahl 2023), the only medication that "should not be combined with lithium" is ACE inhibitor lisinopril (Zestril). Lisinopril is not metabolized and is excreted largely unchanged by the kidneys, with approximately linear pharmacokinetics across typical dosing ranges. ACE inhibition reduces lithium clearance by lowering GFR and increasing proximal tubular sodium (and lithium) reabsorption via angiotensin II and aldosterone suppression. Any decline in renal function therefore increases lithium exposure and toxicity risk.
This interaction is a class effect shared by all ACE inhibitors: increased lithium levels by ~36% plus possibility of delayed toxicity after ~4 wk. Switching to another ACE inhibitor or ARB does not eliminate risk. If an ACE inhibitor is initiated or continued, empiric lithium dose reduction (often ~25–50%) with close serum level and renal monitoring is required.
Lisinopril prescribing info:
❖ Indications
➤ Hypertension
➤ Heart failure / post-MI
➤ Diabetic nephropathy
➤ Preventing CV events
➤ Off-label: May prevent migraines
❖ 2.5, 5, 10, 20, 30, 40 mg unscored tablets
❖ For HTN, start 10 mg QD,max 80 mg
❖ For heart failure, start 2.5–5 mg QD, max 40 mg
❖ With or without food
❖ Combo pills with HCTZ:
➤ Zestoretic, Prinzide
Alternatives to lisinopril that do not interact with lithium
Amlodipine (NORVASC)
❖ Amlodipine 5 mg is usually the cleanest replacement for lisinopril in lithium patients
❖ May increase amlodipine to 10 mg (FDA max)
❖ Onset is gradual – BP effect builds over several days, not hours
❖ No lithium clearance effect – preferred in lithium-treated patients
❖ Long half-life (~40 hr) – steady state in ~7–10 days; avoid rapid up-titration
❖ Edema is dose-limiting (ankle > generalized)
➤ rare at 2.5 mg; common at 10 mg
❖ No renal dose adjustment – safe in CKD
❖ No electrolyte disturbances (no K⁺ or Na⁺ effects)
➤ lab monitoring not needed
❖ Minimal drug–drug interactions (CYP3A4 substrate; clinically modest)
Metoprolol (LOPRESSOR)
❖ Reasonable choice if tachycardia, essential tremor, migraine prophylaxis, CAD, prior MI, or anxiety-related sympathetic excess
❖ Lithium considerations
➤ does not increase lithium levels
➤ may improve lithium-induced tremor
➤ may mask toxicity-related tremor or tachycardia
❖ Start: metoprolol succinate (ER formulation) 50 mg daily
➤ metoprolol tartrate (IR formulation) equivalent (less preferred) is 25 mg BID
➤ if taking strong CYP2D6 inHibitors (e.g., fluoxetine, bupropion, paroxetine) metoprolol exposure may increase ~2–5× (phenoconversion to poor metabolizer) - start 12.5 mg instead or choose propranolol
➤ titrate slowly (≥1 week between adjustments)
➤ higher doses lose β1 selectivity and increase risk of bronchospasm
❖ Do not expect 1:1 BP response
➤ beta blockers often lower BP less than ACEi/CCBs unless sympathetic tone is high
❖ Avoid or down-titrate if resting HR < 55 bpm
➤ caution with AV block or sick sinus syndrome
❖ Adverse effects to counsel
➤ fatigue, exercise intolerance, sexual dysfunction
➤ depressive symptoms uncommon but reported
➤ abrupt discontinuation → rebound tachycardia or angina
Rough BP equivalence: lisinopril 10 mg ≈ metoprolol 50 mg/day ≈ amlodipine 5 mg.
ACE inhibitor | Beta blocker | DHP CCB |
Lisinopril 10 mg daily | Metoprolol 50 mg/day (tartrate 25 mg BID or succinate 50 mg daily) | Amlodipine 5 mg daily |
Lisinopril 20 mg | Metoprolol 100 mg/day | Amlodipine 10 mg |
Lisinopril 40 mg | Metoprolol 200 mg/day | Amlodipine 10 mg (max) |
Metoprolol + amlodipine combination
❖ Preferred combo in lithium-treated patients needing dual therapy
❖ Amlodipine is a CCB that is not contraindicated with beta blockers
➤ unlike non-DHP calcium channel blockers (verapamil, diltiazem), amlodipine does not cause additive AV-nodal blockade
❖ Complementary mechanisms
➤ β-blockade reduces heart rate and sympathetic tone
➤ CCB provides peripheral vasodilation
❖ Additive BP lowering without renal lithium interaction
➤ neither drug reduces lithium clearance
❖ Titration strategy
➤ uptitrate amlodipine first (to 10 mg max) if edema tolerated
➤ uptitrate metoprolol for HR control
Songs
Made with Suno, available on Spotify, etc. Songs have ~4 alt styles. Metoprolol song coming soon.
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