What blood pressure medications, such as thiazide diuretics (e.g. hydrochlorothiazide) or angiotensin-converting enzyme (ACE) inhibitors (e.g. lisinopril), can increase lithium levels in patients with hypertension taking lithium for psychiatric conditions?

Blood Pressure Medications That Increase Lithium Levels

Thiazide diuretics (such as hydrochlorothiazide) are the blood pressure medications most strongly associated with increasing lithium levels, causing a 25-40% increase in lithium concentrations after initiation, while ACE inhibitors (such as lisinopril) also impair lithium elimination but to a lesser and more variable degree. 1

Thiazide Diuretics: Highest Risk

Thiazide diuretics demonstrate the greatest potential to increase lithium concentrations among all antihypertensive classes. 1

• Hydrochlorothiazide and chlorthalidone can elevate lithium levels by 25-40% after therapy initiation, creating significant risk for lithium toxicity 1
• The mechanism involves altered electrolyte exchange in the renal tubule, where thiazides reduce lithium clearance by promoting sodium depletion, which triggers compensatory proximal tubule reabsorption of both sodium and lithium 1
• This interaction is clinically significant because lithium has an extremely narrow therapeutic range—relatively minor increases in serum concentrations may induce serious adverse sequelae 1

ACE Inhibitors: Moderate Risk

ACE inhibitors may impair lithium elimination, though the evidence base is less robust than for thiazides. 1

• Growing evidence suggests ACE inhibitors like lisinopril can reduce lithium clearance, but further investigations are needed to identify which patients are at highest risk 1
• The interaction appears less predictable than with thiazides, with variable effects across individuals 1
• When ACE inhibitors are combined with lithium, close monitoring of lithium levels is warranted, particularly during the first 2-4 weeks after initiation 1

Loop Diuretics and Potassium-Sparing Agents: Minimal Risk

Loop diuretics (furosemide, bumetanide) and potassium-sparing agents (spironolactone, amiloride) have minor variable effects on lithium levels. 1

• These agents act at different sites in the nephron compared to thiazides, resulting in less impact on lithium reabsorption 1
• Loop diuretics may actually increase lithium clearance in some cases, though effects are inconsistent 1

Calcium Channel Blockers and ARBs: No Direct Pharmacokinetic Interaction

Calcium channel blockers like amlodipine and ARBs like losartan do not alter lithium pharmacokinetics through renal mechanisms. 1

• These agents are preferred alternatives when antihypertensive therapy is needed in lithium-treated patients 1
• However, calcium antagonists have been implicated in anecdotal reports of neurotoxicity when combined with lithium, without apparent effects on lithium serum levels—the relative risk appears quite low but caution is advised 1

Clinical Management Algorithm

When prescribing antihypertensives to patients on lithium:

1. First-line choices: Use calcium channel blockers or ARBs, which lack direct pharmacokinetic interactions with lithium 1

2. If ACE inhibitors are needed: Monitor lithium levels at baseline, then 1-2 weeks after initiation, and monthly for the first 3 months 1

3. Avoid thiazide diuretics when possible: If thiazides are clinically necessary (e.g., for resistant hypertension), expect a 25-40% increase in lithium levels and reduce lithium dose preemptively by 25-30%, with close monitoring 1

4. Monitor for lithium toxicity symptoms: Tremor, confusion, ataxia, polyuria, and gastrointestinal symptoms warrant immediate lithium level assessment regardless of medication changes 1

Critical Pitfall to Avoid

Never assume lithium levels will remain stable when adding any diuretic or ACE inhibitor—proactive monitoring is essential because lithium toxicity can develop rapidly and has serious neurological consequences. 1 The narrow therapeutic index of lithium (0.6-1.2 mEq/L therapeutic range) means that drug interactions causing even modest increases in serum concentrations can precipitate toxicity 1.