What are the potential drug interactions with Angiotensin-Converting Enzyme (ACE) inhibitors?

Drug Interactions for ACE Inhibitors

Critical Drug Interactions Requiring Immediate Action

Potassium-Sparing Agents and Supplements

ACE inhibitors combined with potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium supplements, or potassium-containing salt substitutes can cause life-threatening hyperkalemia and should generally be avoided, especially in patients with heart failure or renal insufficiency. 1

• Hyperkalemia occurs in approximately 1% of hypertensive patients and 3.8% of heart failure patients on ACE inhibitors 1
• Risk factors include renal insufficiency (GFR <60 mL/min), diabetes mellitus, and concomitant use of potassium-containing products 1, 2
• Monitor serum potassium within 1-2 weeks after initiation and after any dose changes 3
• Potassium-sparing agents should generally not be used in heart failure patients receiving ACE inhibitors 1

Dual RAAS Blockade

Do not combine ACE inhibitors with angiotensin receptor blockers (ARBs) or aliskiren—this dual blockade increases risks of hypotension, hyperkalemia, and acute renal failure without providing additional clinical benefit. 1

• Specifically avoid aliskiren with ACE inhibitors in diabetic patients entirely 1
• Avoid aliskiren with ACE inhibitors in patients with renal impairment (GFR <60 mL/min) 1
• Closely monitor blood pressure, renal function, and electrolytes if dual therapy cannot be avoided 1

NSAIDs and COX-2 Inhibitors

Nonsteroidal anti-inflammatory drugs block the favorable effects and enhance the adverse effects of ACE inhibitors—avoid NSAIDs unless absolutely essential. 3

• NSAIDs can cause acute renal failure when combined with ACE inhibitors, particularly in elderly, volume-depleted patients, or those with compromised renal function 1, 4
• NSAIDs attenuate the antihypertensive effect of ACE inhibitors 1, 5
• NSAIDs reduce renal excretion of ACE inhibitors, increasing circulating drug concentrations 5
• Monitor renal function periodically in patients receiving both agents 1
• If ibuprofen must be used with aspirin, take ibuprofen at least 30 minutes after immediate-release aspirin or at least 8 hours before aspirin 3

Lithium

ACE inhibitors can cause lithium toxicity by reducing renal lithium clearance—use this combination with extreme caution and monitor lithium levels frequently. 1, 4, 5

• Lithium toxicity has been reported in patients receiving ACE inhibitors with drugs that cause sodium elimination 1
• Frequent monitoring of lithium concentrations is mandatory with all ACE inhibitors 5

Hypotension-Related Interactions

Diuretics

Patients on diuretics, especially those recently initiated, may experience excessive hypotension when starting ACE inhibitors—consider discontinuing the diuretic or increasing salt intake 2-3 days before starting the ACE inhibitor. 1, 4

• If diuretic must be continued, provide close medical supervision for at least 2 hours after the initial ACE inhibitor dose and until blood pressure stabilizes for an additional hour 1
• Start with low doses: captopril 6.25 mg three times daily, enalapril 2.5 mg twice daily, or lisinopril 2.5-5 mg once daily 3, 6
• The combination itself does not cause pharmacokinetic interactions, but pharmacodynamic effects require careful monitoring 5

Antipsychotic Medications

When combining ACE inhibitors with antipsychotics, start ACE inhibitors at low doses and monitor blood pressure including orthostatic measurements at baseline, after initiation, after dose increases, and periodically during maintenance. 6

• Consider high-potency antipsychotics like risperidone to minimize additive hypotensive effects 6
• Assess volume status before initiating ACE inhibitors in patients taking antipsychotics 6
• Titrate gradually to target doses used in clinical trials, monitoring for hypotension at each step 6

Other Cardiovascular Agents

ACE inhibitors can be used safely with beta-blockers, methyldopa, nitrates, calcium channel blockers, hydralazine, prazosin, and digoxin without clinically significant adverse interactions 1

• The antihypertensive effect is augmented by agents that cause renin release (e.g., diuretics) 1
• No evidence suggests increased risk of digitalis toxicity when ACE inhibitors are combined with digoxin 5

Aspirin-ACE Inhibitor Controversy

Despite theoretical concerns, aspirin should be administered with ACE inhibitors when there is a clear indication for aspirin use, as the benefits outweigh potential interaction risks. 3

• Aspirin may attenuate hemodynamic actions of ACE inhibitors through inhibition of kinin-mediated prostaglandin synthesis 3
• Retrospective analyses show ACE inhibitors remain significantly beneficial in patients taking aspirin (20% risk reduction) versus those not taking aspirin (29% risk reduction)—a difference not reaching statistical significance 3
• Clopidogrel does not interact with ACE inhibitors and may be considered as an alternative antiplatelet agent, though it lacks indication for primary prevention of ischemic events 3
• The proposed negative interaction does not appear to interfere importantly with clinical benefits of either agent 3

Venom Immunotherapy (VIT) Considerations

ACE inhibitors increase the risk of severe anaphylaxis during venom immunotherapy—consider discontinuing ACE inhibitors and substituting an equally efficacious alternative (such as an ARB) before starting VIT. 3

• A large multicenter study found ACE inhibitor exposure associated with statistically significant increased risk of more severe anaphylaxis during VIT 3
• ACE inhibitors impair breakdown of vasoactive kinins (bradykinin) generated during anaphylaxis 3
• Hymenoptera venom package inserts contain warnings about life-threatening anaphylactic reactions in patients on ACE inhibitors 3
• Angiotensin receptor blockers do not carry this risk and do not need to be suspended for VIT 3
• If ACE inhibitor is required for an indication with no equally effective alternative, approach VIT cautiously with individualized risk/benefit assessment 3

Surgery and Anesthesia

ACE inhibitors may block compensatory angiotensin II formation during surgery or anesthesia with hypotensive agents—if hypotension occurs, correct with volume expansion. 1

• ACE inhibitors can block angiotensin II formation secondary to compensatory renin release during major surgery 1

Renal Function Monitoring

Monitor renal function and electrolytes within 1-2 weeks after ACE inhibitor initiation and after any dose increase, particularly in high-risk patients. 3, 1

• High-risk patients include those with systolic blood pressure <80 mmHg, low serum sodium, diabetes mellitus, and impaired renal function 3
• Major dosage adjustments are necessary only when GFR falls below 30 mL/min 7
• Renal clearance may be reduced in elderly patients with mild renal dysfunction or congestive heart failure 5

Food and Antacid Interactions

Bioavailability of ACE inhibitors is reduced by concomitant food or antacids, which slow gastric emptying and raise gastric pH 5

Common Pitfalls to Avoid

• Failing to discontinue or reduce diuretics before starting ACE inhibitors in volume-depleted patients 1, 4
• Prescribing potassium supplements or potassium-sparing diuretics without close monitoring in patients with renal insufficiency or diabetes 1, 2
• Allowing patients to use over-the-counter NSAIDs without physician supervision 3, 1
• Not monitoring lithium levels frequently when combining with ACE inhibitors 1, 5
• Combining ACE inhibitors with ARBs or aliskiren expecting additional benefit 1
• Failing to recognize acute methamphetamine intoxication before administering beta-blockers (though this is a beta-blocker interaction, not ACE inhibitor-specific) 8