What are the side effects of Angiotensin-Converting Enzyme (ACE) inhibitors?

Side Effects of ACE Inhibitors

The most common side effects of ACE inhibitors include cough (occurring in 5-20% of patients), hypotension, renal insufficiency, hyperkalemia, angioedema, and syncope. 1, 2, 3

Common Side Effects

Cough

• Occurs in 5-20% of patients taking ACE inhibitors 1, 2
• Typically dry, tickly, and often bothersome 1
• More common in:
  • Women (79% of cough cases) 4
  • Nonsmokers 1
  • Asian and Chinese patients 1, 2
• Not dose-dependent 1, 4
• May develop within hours of first dose or be delayed for weeks to months 1
• Usually resolves within 1-4 weeks after discontinuation (though can persist up to 3 months) 1
• Mechanism: Related to inhibition of kininase II, leading to accumulation of bradykinin, substance P, and prostaglandins 1, 5

Hypotension

• Most common in patients with:
  • Heart failure (6.7% incidence vs. 0.6% in placebo) 3
  • Hyponatremia 3
  • High-dose diuretic therapy 3
  • Recent intensive diuresis 3
  • Renal dialysis 3
  • Severe volume/salt depletion 3
• Most frequent during first few days of therapy or after dose increases 2
• Management: Consider reducing diuretic dose, liberalizing salt intake if no fluid retention, and staggering doses of other hypotensive medications 2

Renal Effects

• Increases in blood urea nitrogen and serum creatinine occur in about 0.2% of hypertensive patients and 11% of heart failure patients 3
• More likely in patients receiving concomitant diuretics or with renal artery stenosis 3
• Acute renal failure can occur in conditions where glomerular filtration is dependent on angiotensin II-mediated efferent vascular tone (post-stenotic kidney, heart failure with volume depletion) 6
• Usually reversible upon discontinuation of the drug 3, 6

Hyperkalemia

• Risk factors include:
  • Renal impairment 2, 7
  • Concomitant use of potassium-sparing diuretics 7
  • Potassium supplements 2
  • Diabetes 2

Serious but Less Common Side Effects

Angioedema

• Occurs in <1% of patients taking ACE inhibitors 1
• More frequent in Black patients 1, 2
• Can affect face, extremities, lips, tongue, glottis, and/or larynx 3
• Can be life-threatening when involving the airway 3
• Requires immediate discontinuation of ACE inhibitor and appropriate therapy 3
• Intestinal angioedema can also occur, presenting with abdominal pain 3
• Absolute contraindication to future ACE inhibitor use 2

Hematologic Effects

• Small decreases in hemoglobin and hematocrit (rarely of clinical importance) 3
• Rare cases of neutropenia, thrombocytopenia, and bone marrow depression 3
• Hemolytic anemia (including cases in patients with G-6-PD deficiency) 3

Hepatic Effects

• Rare cases of hepatic failure, hepatitis (hepatocellular or cholestatic jaundice) 3

Other Side Effects

Gastrointestinal

• Diarrhea (2.1% in heart failure patients) 3
• Nausea (1.3%) 3
• Vomiting (1.3%) 3
• Ileus, pancreatitis (rare) 3

Neurological/Psychiatric

• Dizziness (7.9% in heart failure patients) 3
• Headache (1.8%) 3
• Vertigo (1.6%) 3
• Depression, confusion, ataxia, somnolence (rare) 3

Respiratory (besides cough)

• Bronchospasm (rare, but can occur in patients with obstructive airways disease) 5
• Rhinorrhea, sore throat, hoarseness 3
• Eosinophilic pneumonitis (rare) 3

Dermatologic

• Rash (1.3% in heart failure patients) 3
• Rare but serious: Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome 3

Contraindications

• Previous angioedema with ACE inhibitor therapy 1, 2
• Pregnancy 1, 2
• Bilateral renal artery stenosis 1, 2

Monitoring Recommendations

• Renal function and serum potassium should be monitored:
  • Before starting therapy 1
  • 1-2 weeks after each dose increment 1, 2
  • At 3-6 month intervals 1
  • When adding other treatments that may affect renal function 1
  • More frequently in patients with renal dysfunction or electrolyte disturbances 1, 2

Management of Side Effects

• For cough: Discontinuation is the only uniformly effective treatment 1
• For hypotension: Reduce diuretic dose if possible, increase salt intake if no fluid retention 2
• For angioedema: Immediate discontinuation of ACE inhibitor; subcutaneous epinephrine solution 1:1000 (0.3-0.5 mL) for airway involvement 3
• For hyperkalemia: Regulate dietary potassium intake 8
• For worsening renal function: May need to be tolerated to maintain therapy; usually improves after reduction in diuretic dose 2

When ACE inhibitor side effects necessitate discontinuation, angiotensin receptor blockers (ARBs) may be considered as an alternative, particularly for patients with cough, though caution is advised when substituting an ARB in patients with ACE inhibitor-associated angioedema 1, 2.