What are the risks and recommendations for using lithium with benazepril (Angiotensin-Converting Enzyme (ACE) inhibitor) or propranolol (beta blocker) in a patient with bipolar disorder and hypertension?

Lithium and Benazepril or Propranolol: Drug Interaction Risks and Management

Direct Recommendation for ACE Inhibitors (Benazepril)

The combination of lithium and benazepril carries significant risk of lithium toxicity and requires intensive monitoring, dose reduction of lithium by 25-40%, and avoidance of concurrent thiazide diuretics—this combination should only be used when absolutely necessary and with weekly lithium level monitoring during initiation. 1, 2, 3

Mechanism and Risk Profile

• ACE inhibitors like benazepril reduce renal clearance of lithium by decreasing glomerular filtration and altering sodium handling in the nephron, leading to 25-40% increases in serum lithium concentrations. 2
• The FDA drug label explicitly warns that "caution should be used when lithium and ACE inhibitors are used concomitantly because sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity." 1
• Lithium toxicity has been reported in patients receiving lithium concomitantly with ACE inhibitors, though it is usually reversible upon discontinuation. 1

Critical Management Algorithm When Combination is Necessary

If benazepril must be combined with lithium:

• Reduce lithium dose by 25-40% preemptively before initiating benazepril. 2
• Check lithium levels weekly for the first month, then every 2 weeks for 2 months, then monthly once stable. 4, 3
• Ensure adequate hydration (2500-3000 mL daily) and normal salt intake, as sodium depletion dramatically increases lithium toxicity risk. 4, 3
• Absolutely avoid concurrent thiazide diuretics (hydrochlorothiazide), which have the greatest potential to increase lithium concentrations by 25-40% and create a dangerous triple interaction. 2, 3
• Monitor for early signs of lithium toxicity: diarrhea, vomiting, tremor, mild ataxia, drowsiness, or muscular weakness—patients must discontinue lithium and contact physician immediately if these occur. 4

Evidence from Clinical Cases

• Three case reports demonstrated that lithium intoxication occurred when ACE inhibitors were combined with either hydrochlorothiazide or dehydration, suggesting the combination is possible when sufficient hydration is ensured and thiazide diuretics are avoided. 3
• These cases indicate that dehydration is a necessary cofactor for lithium toxicity when combined with ACE inhibitors, emphasizing the critical importance of maintaining adequate fluid intake. 3

---

Direct Recommendation for Beta-Blockers (Propranolol)

The combination of lithium and propranolol is generally safe from a pharmacokinetic perspective, as beta-blockers do not significantly alter lithium clearance—however, monitor for additive CNS effects (tremor, sedation) and cardiovascular effects (bradycardia), particularly during initial combination. 4, 5

Safety Profile

• Beta-blockers do not affect renal lithium clearance or glomerular filtration rates, making them pharmacokinetically compatible with lithium. 2, 5
• No significant drug-drug interactions between lithium and beta-blockers have been documented in the literature regarding lithium levels or toxicity risk. 2
• The 2024 ESC Guidelines recommend beta-blockers be combined with other antihypertensive classes when there are compelling indications such as angina, post-myocardial infarction, or heart rate control. 6

Monitoring Requirements

When combining lithium with propranolol:

• Monitor for additive tremor, as both lithium and propranolol can cause tremor independently—fine tremor is common with therapeutic lithium levels. 4
• Check for excessive bradycardia or hypotension, particularly in elderly patients or those on multiple cardiovascular medications. 5
• Maintain standard lithium monitoring: levels every 3-6 months once stable, with renal and thyroid function testing. 7, 4
• No preemptive lithium dose reduction is necessary when adding propranolol, unlike with ACE inhibitors. 2

Preferred Antihypertensive Combinations

• If choosing between benazepril and propranolol for a patient on lithium, propranolol is the safer choice from a drug interaction perspective. 2, 5
• For uncomplicated hypertension in bipolar patients on lithium, consider calcium channel blockers (dihydropyridines like amlodipine) as first-line, as they have minimal interaction with lithium and proven cardiovascular benefits. 6, 2
• The 2024 ESC Guidelines recommend ACE inhibitors or ARBs combined with dihydropyridine calcium channel blockers or diuretics as preferred combinations for most patients, but in lithium-treated patients, the calcium channel blocker + beta-blocker combination avoids the ACE inhibitor-lithium interaction entirely. 6

---

Common Pitfalls to Avoid

• Never combine lithium with thiazide diuretics and ACE inhibitors simultaneously—this triple combination creates extreme risk of lithium toxicity. 2, 3
• Do not assume all diuretics have equal risk: thiazides have the greatest potential (25-40% increase in lithium levels), loop diuretics have minor variable effects, and potassium-sparing agents have minimal effects. 2
• Avoid NSAIDs in patients on lithium, as indomethacin and piroxicam significantly increase steady-state lithium concentrations, and even COX-2 inhibitors increase lithium levels by approximately 17%. 4, 1, 2
• Never discontinue lithium abruptly if toxicity develops—taper gradually over 2-4 weeks minimum to prevent rebound mania, which occurs in >90% of patients with abrupt discontinuation. 7
• Educate patients that protracted sweating, diarrhea, or fever with infection may necessitate temporary lithium dose reduction, as these conditions increase lithium toxicity risk through sodium and fluid depletion. 4

---

Optimal Hypertension Management Strategy in Bipolar Patients on Lithium

The safest algorithmic approach:

1. First-line: Dihydropyridine calcium channel blocker (amlodipine) monotherapy or combined with beta-blocker if needed for rate control or compelling indication. 6, 2
2. Second-line: Add beta-blocker (propranolol, metoprolol) if additional blood pressure control needed—no lithium dose adjustment required. 6, 5
3. Third-line: If ACE inhibitor absolutely necessary (e.g., diabetic nephropathy, heart failure), reduce lithium dose by 25-40%, ensure adequate hydration, avoid thiazides, and implement weekly lithium monitoring. 1, 2, 3
4. Avoid: Thiazide diuretics entirely in lithium-treated patients; if diuresis needed, use loop diuretics with close monitoring. 2