What are the side effects of lisinopril (angiotensin-converting enzyme (ACE) inhibitor)?

Side Effects of Lisinopril

The most common side effects of lisinopril include cough (occurring in 5-20% of patients), hypotension, dizziness, worsening renal function, and hyperkalemia, with cough being the leading cause of discontinuation despite the drug's proven mortality benefits in cardiovascular disease. 1, 2, 3

Common Side Effects

Respiratory Effects

• Cough:
  • Occurs in 5-20% of patients, more common in women and Asian patients (up to 50% in Chinese patients) 1, 2
  • Typically dry, non-productive with a persistent tickling sensation in the throat 1
  • Usually appears within the first months of therapy but can occur within hours of first dose 1
  • Resolves within 1-4 weeks after discontinuation, but may persist up to 3 months 1
  • Most common reason for withdrawal of ACE inhibitor therapy 1

Cardiovascular Effects

• Hypotension: Most common adverse effect in heart failure patients 1, 3
  • Blood pressure declines in nearly all patients, but symptomatic hypotension occurs most frequently during:
    • First few days of therapy
    • After dose increases
    • In patients with hypovolemia
    • After recent diuresis
    • In patients with severe hyponatremia (serum sodium <130 mmol/L) 1
• Chest pain: Reported in clinical trials (2.1% higher than placebo in heart failure patients) 3

Renal Effects

• Worsening renal function:
  • Significant increase in serum creatinine (>0.3 mg/dL) observed in:
    • 15-30% of patients with severe heart failure
    • 5-15% of patients with mild to moderate symptoms 1
  • Risk factors include:
    • Bilateral renal artery stenosis
    • Use of NSAIDs
    • Advanced heart failure (class IV)
    • Hyponatremia 1

Metabolic Effects

• Hyperkalemia:
  • Can be severe enough to cause cardiac conduction disturbances 1
  • More common in patients with:
    • Renal dysfunction
    • Taking potassium supplements
    • Taking potassium-sparing diuretics
    • Diabetes mellitus 1, 2

Serious but Less Common Side Effects

Immunologic/Dermatologic

• Angioedema:
  • Occurs in <1% of patients but more frequent in Black patients 2
  • Can be life-threatening
  • Requires permanent discontinuation of all ACE inhibitors 1, 2
• Skin reactions: Rash, urticaria, photosensitivity, toxic epidermal necrolysis, Stevens-Johnson syndrome 3

Hematologic

• Blood disorders: Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia, thrombocytopenia 3

Other Reported Side Effects

• Gastrointestinal: Pancreatitis, constipation, flatulence, dry mouth, diarrhea 3
• Neurological: Headache, taste disturbances, vertigo, paresthesia 3
• Sensory: Visual loss, diplopia, blurred vision, tinnitus, photophobia 3
• Endocrine: Diabetes mellitus, inappropriate antidiuretic hormone secretion 3
• Urogenital: Impotence 3
• Other: Fatigue, asthenia, orthostatic effects 3

Management of Side Effects

Hypotension

• Reduce diuretic dose if possible
• Liberalize salt intake if no significant fluid retention
• Stagger doses of other hypotensive medications 1

Worsening Renal Function

• Usually improves after reduction in diuretic dose
• May need to tolerate mild to moderate azotemia to maintain ACE inhibitor therapy 1

Cough

• Consider other causes of cough (especially pulmonary congestion) before attributing to lisinopril
• If cough is not severe, encourage continuation due to long-term benefits
• If persistent and troublesome, consider switching to an angiotensin receptor blocker (ARB) 1

Special Considerations

• In clinical trials, despite side effects, only 5.7% of hypertensive patients and 11% of heart failure patients discontinued lisinopril due to adverse reactions 3
• Serious adverse events were actually lower with ACE inhibitors compared to placebo in heart failure trials (57.3% vs 63.0%) 1
• Risk of side effects increases with renal impairment, requiring dose adjustment when creatinine clearance is <30 mL/min 4

Remember that despite these side effects, lisinopril has proven mortality benefits in cardiovascular disease, and many side effects can be managed without discontinuing therapy.