What are the potential side effects of Angiotensin Receptor Blockers (ARB)/Angiotensin-Converting Enzyme (ACE) inhibitors in patients with hypertension, heart failure, or diabetic nephropathy, particularly those with pre-existing renal impairment?

Side Effects of ACE Inhibitors and ARBs

Most Common Side Effects

ACE inhibitors cause cough in 5-10% of white patients and up to 50% in Chinese patients, presenting as a dry, tickling sensation in the throat that typically resolves within 1-4 weeks of discontinuation. 1 This occurs more frequently than with ARBs because ACE inhibitors inhibit kininase and increase bradykinin levels. 2 ARBs are associated with a much lower incidence of cough since they do not affect kininase. 2

• Fatigue occurs in approximately 7% of patients on ACE inhibitors. 1
• Angioedema occurs in <1% of patients but is life-threatening, with higher frequency in Black patients and women. 2, 1 ARBs have a much lower incidence of angioedema compared to ACE inhibitors. 2
• Discontinuation rates are approximately 5% for both drug classes, most commonly due to cough (ACE inhibitors) or headache. 1

Serious Adverse Effects Related to Angiotensin Suppression

Hypotension

Blood pressure declines occur in nearly every patient, but symptomatic hypotension is the primary concern, particularly in volume-depleted patients, those on recent marked diuresis, or with severe hyponatremia (sodium <130 mmol/L). 1

• Symptomatic hypotension occurs in 15.9% of patients. 1
• Risk is highest when initiating therapy in patients already on diuretics. 3, 4
• Management approach: Reduce diuretic doses, liberalize salt intake, or reduce/stagger other hypotensive agents to avoid peak effect overlap before starting ACE inhibitor or ARB therapy. 1, 3

Renal Dysfunction

ACE inhibitors and ARBs should be given with caution to patients with renal insufficiency, as glomerular filtration becomes critically dependent on angiotensin II-mediated efferent arteriolar vasoconstriction in states of reduced renal perfusion. 2, 1

• Significant increases in serum creatinine (>0.3 mg/dL) occur in 15-30% of patients with severe heart failure, but only 5-15% with mild to moderate symptoms. 1
• Both drug classes are contraindicated in bilateral renal artery stenosis. 2, 1
• Monitoring protocol: Check renal function before initiation, 1-2 weeks after each dose increment, at 3-6 month intervals, and when adding other medications affecting renal function (aldosterone antagonists, NSAIDs). 2, 1

Hyperkalemia

Hyperkalemia can be sufficiently severe to cause cardiac conduction disturbances, particularly in patients with deteriorating renal function, those taking potassium supplements, potassium-sparing diuretics, aldosterone antagonists, or patients with diabetes. 1

• The absolute increase in hyperkalemia frequency is 2.3% compared to placebo. 1
• Up to 10% of patients may experience at least mild hyperkalemia. 5
• High-risk populations: Patients with chronic renal insufficiency (eGFR <60 mL/min/1.73 m²), those on potassium-sparing diuretics, or with excessive dietary potassium intake. 2, 3, 5
• Monitoring: Check serum potassium within 2-4 weeks of initiation or dose change, then at least annually in stable patients, more frequently in high-risk patients. 2, 3

Critical Drug Interactions

Potassium-Sparing Diuretics

Concurrent use of potassium-sparing diuretics (spironolactone, amiloride, triamterene) markedly increases hyperkalemia risk and should be avoided or used with extreme caution. 1, 3

• Monitor serum potassium frequently if combination therapy is necessary. 3

NSAIDs (Including COX-2 Inhibitors)

In elderly patients, volume-depleted patients, or those with compromised renal function, coadministration of NSAIDs with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. 6, 3, 4

• These effects are usually reversible. 3
• NSAIDs may also attenuate the antihypertensive effect of ACE inhibitors and ARBs. 6, 3

Dual RAS Blockade (ACE Inhibitor + ARB)

Never combine ACE inhibitors and ARBs, as dual blockade is associated with increased risks of hypotension, syncope, hyperkalemia, and acute renal failure compared to monotherapy, with no additional cardiovascular or kidney disease benefits. 6, 3

• The VA NEPHRON-D trial demonstrated that combination losartan and lisinopril therapy resulted in increased incidence of hyperkalemia and acute kidney injury without additional benefit. 6
• Do not coadminister aliskiren with ACE inhibitors or ARBs in patients with diabetes or renal impairment (GFR <60 mL/min). 6, 3

Lithium

Lithium toxicity has been reported with concurrent ACE inhibitor or ARB use due to reduced sodium elimination. 3, 4

• Monitor serum lithium levels during concurrent use. 6, 3

Antidiabetic Medications

Concomitant administration of ACE inhibitors with insulin or oral hypoglycemic agents may cause an increased blood-glucose-lowering effect with risk of hypoglycemia. 3

Special Populations and Contraindications

Pregnancy

ACE inhibitors and ARBs are contraindicated in pregnancy and should be used with caution in women of childbearing potential. 2

• ARBs are classified as class C/D in pregnancy. 2

Patients with Advanced Renal Disease

In patients with advanced renal disease, even without renal artery stenosis, ACE inhibitors may cause rapid decline in renal function. 2

• Whether this occurs with ARBs is less well established. 2

Common Pitfalls to Avoid

• Do not prescribe ACE inhibitors or ARBs solely for "cardioprotection" in diabetic patients without kidney disease or hypertension, as clinical trials show no benefit and one trial demonstrated increased cardiovascular events. 7
• Avoid abrupt withdrawal of ACE inhibition, as this can lead to clinical deterioration. 2
• Do not assume ARBs are superior to ACE inhibitors for cardiovascular outcomes—ACE inhibitors have overwhelming data showing substantial cardiovascular risk reduction in type 2 diabetes, while similar data for ARBs are limited. 8
• Monitor for angioedema history before prescribing—patients with prior angioedema to any ACE inhibitor should not receive ACE inhibitors again. 1

Clinical Context and Benefit-Risk Profile

Despite these adverse effects, both ACE inhibitors and ARBs demonstrate favorable benefit-risk profiles. 1 Patients on ACE inhibitors experience significantly lower rates of serious adverse events (57.3% vs 63.0% with placebo), with only modest increases in overall adverse event burden (87.0% vs 82.0%, absolute difference +5%). 1 Most adverse effects are manageable with dose adjustments and careful monitoring. 1