What antihypertensive medication would be most concerning to add to a patient's regimen who is on long-term lithium (lithium) therapy for bipolar disorder?

Thiazide Diuretics Are the Most Concerning Antihypertensive to Add for a Patient on Long-term Lithium Therapy

Thiazide diuretics should be avoided in patients on long-term lithium therapy due to their significant risk of increasing lithium levels and precipitating lithium toxicity.

Mechanism of Interaction Between Thiazide Diuretics and Lithium

Thiazide diuretics pose the greatest concern among antihypertensive medications for patients on lithium therapy due to their specific effects on renal handling of lithium:

• Thiazide diuretics have demonstrated the greatest potential to increase lithium concentrations, with a 25-40% increase in lithium levels often evident after initiation of therapy 1
• The interaction occurs because thiazides act on the distal tubule of the kidney, where they reduce sodium and water excretion, leading to increased lithium reabsorption
• This pharmacokinetic interaction significantly narrows lithium's already limited therapeutic window

Comparative Risk Among Antihypertensive Classes

When considering antihypertensive options for patients on lithium therapy, the relative risks are:

1. Highest risk: Thiazide diuretics
2. Moderate risk: ACE inhibitors and ARBs (can impair lithium elimination but to a lesser extent than thiazides) 1
3. Lower risk: Calcium channel blockers (some case reports of neurotoxicity but pharmacokinetic interaction is minimal) 1
4. Lowest risk: Beta-blockers (except metoprolol, which should be avoided in psychiatric patients with drug-induced tachycardia) 2

Consequences of Lithium-Thiazide Interaction

The interaction between lithium and thiazide diuretics can lead to:

• Acute lithium toxicity with symptoms including tremor, ataxia, confusion, and seizures
• Worsening of chronic lithium-induced nephropathy, which is already a concern after 3 years of therapy 3
• Increased risk of requiring dialysis in the long term 3, 4

Recommended Antihypertensive Approaches for Patients on Lithium

Based on the 2020 International Society of Hypertension guidelines 2, the preferred antihypertensive medications for patients on lithium therapy are:

• First choice: RAS inhibitors (ACEIs/ARBs) with careful monitoring of lithium levels
• Second choice: Calcium channel blockers (with caution in patients with orthostatic hypotension)
• Third choice: Beta-blockers (non-metoprolol)

Monitoring Recommendations When Adding Any Antihypertensive

If an antihypertensive must be added to a patient on long-term lithium therapy:

• Check serum lithium levels before initiating the antihypertensive
• Recheck lithium levels 5-7 days after starting the antihypertensive
• Monitor for signs of lithium toxicity (tremor, confusion, ataxia, seizures)
• Consider more frequent monitoring of renal function, as patients on lithium for 3+ years already have increased risk of chronic kidney disease 3, 5

Clinical Implications of Lithium Discontinuation

It's important to note that discontinuing lithium in patients with bipolar disorder who develop renal issues carries significant risks:

• Patients who discontinue lithium after CKD diagnosis have a higher risk of mood episode relapse (HR 8.38) 6
• The decision to discontinue lithium should be carefully weighed against psychiatric stability

Conclusion

When managing hypertension in a patient on long-term lithium therapy, thiazide diuretics pose the greatest risk of precipitating lithium toxicity and should be avoided. Alternative antihypertensive classes, particularly calcium channel blockers or beta-blockers (non-metoprolol), represent safer options with appropriate monitoring.