What are the potential side effects of lisinopril (angiotensin-converting enzyme (ACE) inhibitor) in adults with hypertension or heart failure, particularly those with pre-existing kidney issues?

Lisinopril Side Effects

Lisinopril is generally well tolerated, but clinicians must monitor for life-threatening angioedema, hypotension, renal dysfunction, and hyperkalemia, particularly in patients with pre-existing kidney disease, heart failure, or volume depletion. 1

Life-Threatening Adverse Reactions (Absolute Contraindications)

Angioedema is the most serious side effect and can be fatal:

• Involves face, extremities, lips, tongue, glottis, and/or larynx 1
• Can occur at any time during treatment 1
• Patients with tongue, glottis, or laryngeal involvement are at high risk for airway obstruction, especially those with prior airway surgery 1
• Black patients have a higher rate of angioedema compared to non-Black patients 1
• Lisinopril must be discontinued immediately if angioedema occurs 1
• History of angioedema (even unrelated to ACE inhibitors) is an absolute contraindication 2

Anuric renal failure during previous ACE inhibitor exposure is an absolute contraindication 2

Pregnancy is an absolute contraindication—lisinopril causes fetal toxicity, oligohydramnios, fetal lung hypoplasia, skeletal deformations, skull hypoplasia, anuria, hypotension, renal failure, and death 1

Renal and Electrolyte Complications

Renal dysfunction is a critical concern requiring close monitoring:

• Occurs in approximately 2% of hypertensive patients treated with lisinopril alone 1
• Risk increases to 11.6% in heart failure patients on concomitant diuretics 1
• Patients with acute MI have 2.4% incidence (vs 1.1% placebo) of renal dysfunction, defined as creatinine >3 mg/dL or doubling of baseline 1
• Renal function should be assessed within 1-2 weeks of initiation and periodically thereafter 2, 3

High-risk patients for renal complications include those with:

• Renal artery stenosis (especially bilateral) 2
• Chronic kidney disease 1
• Severe heart failure 1
• Post-myocardial infarction 1
• Volume depletion 1
• Baseline creatinine >3 mg/dL (use with extreme caution) 2

Hyperkalemia develops due to reduced aldosterone secretion:

• Occurred in 2.2% of hypertensive patients and 4.8% of heart failure patients (defined as K+ >5.7 mEq/L) 1
• Risk factors include renal insufficiency, diabetes, concomitant potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes 1
• Use with caution if baseline potassium >5.5 mmol/L 2
• Monitor potassium within 1-2 weeks of initiation and periodically thereafter 2, 3

Cardiovascular Side Effects

Hypotension is common and can be severe:

• Occurred 3.8% more frequently than placebo in heart failure patients 1
• Patients with acute MI had 5.3% higher incidence compared to those not taking lisinopril 1
• Symptomatic hypotension can be complicated by oliguria, progressive azotemia, acute renal failure, or death 1

High-risk patients for hypotension include those with:

• Systolic blood pressure <80 mm Hg 2
• Heart failure with systolic BP <100 mmHg 1
• Ischemic or cerebrovascular disease 1
• Hyponatremia 1
• High-dose diuretic therapy 1
• Renal dialysis 1
• Severe volume/salt depletion 1
• Severe aortic stenosis or hypertrophic cardiomyopathy 1

Common Non-Life-Threatening Side Effects

Most frequent adverse events in controlled trials (≥2% greater than placebo):

• Headache (3.8% more than placebo) 1
• Dizziness (3.5% more than placebo) 1
• Cough (2.5% more than placebo)—a class effect of ACE inhibitors 1
• Chest pain (2.1% more than placebo in heart failure patients) 1
• Fatigue and asthenia 1

Gastrointestinal effects:

• Diarrhea 1, 4
• Constipation, flatulence, dry mouth 1
• Pancreatitis (rare) 1

Hematologic effects:

• Small decreases in hemoglobin (mean 0.4 g%) and hematocrit (mean 1.3 vol%) occur frequently but are rarely clinically significant 1
• Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia 1

Hepatic and Metabolic Effects

Hepatic failure is rare but serious:

• ACE inhibitors associated with syndrome starting with cholestatic jaundice or hepatitis progressing to fulminant hepatic necrosis and sometimes death 1
• Discontinue immediately if jaundice or marked hepatic enzyme elevations develop 1

Metabolic disturbances:

• Hyponatremia 1
• Hypoglycemia in diabetic patients on oral antidiabetic agents or insulin 1
• Gout 1

Dermatologic and Immunologic Reactions

Skin reactions:

• Urticaria, alopecia, photosensitivity, erythema, flushing, diaphoresis 1
• Rare but serious: toxic epidermal necrolysis, Stevens-Johnson syndrome 1
• Psoriasis 1
• Pruritus 1

Autoimmune-like syndrome:

• Positive ANA, elevated ESR, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, leukocytosis, paresthesia, vertigo 1
• May occur with or without rash 1

Special Anaphylactoid Reactions

During desensitization therapy:

• Life-threatening anaphylactoid reactions occurred in patients receiving hymenoptera venom desensitization while on ACE inhibitors 1

During dialysis:

• Sudden, potentially life-threatening reactions with high-flux membranes 1
• Dialysis must be stopped immediately and aggressive therapy initiated 1
• Antihistamines do not relieve symptoms 1
• Consider different dialysis membrane or different antihypertensive class 1

During LDL apheresis:

• Anaphylactoid reactions reported with dextran sulfate absorption 1

Monitoring Requirements to Detect Side Effects

Essential monitoring parameters:

• Renal function (creatinine) within 1-2 weeks of initiation, after dose increases, and periodically thereafter 2, 3
• Serum potassium within 1-2 weeks of initiation, after dose increases, and periodically thereafter 2, 3
• Blood pressure to detect hypotension 3
• More frequent monitoring required in patients with pre-existing hypotension, hyponatremia, diabetes, azotemia, or those taking potassium supplements 2, 3

Tolerability Profile

Overall tolerability:

• 85-90% of heart failure patients tolerate short- and long-term therapy 2
• In hypertension trials, 5.7% discontinued due to adverse reactions 1
• In heart failure trials, 11% discontinued over up to 4 years, with 8.1% discontinuing in 12-week controlled studies vs 7.7% on placebo 1
• High doses (32.5-35 mg) and low doses (2.5-5 mg) had similar discontinuation rates despite higher incidence of hypotension and renal dysfunction with high doses 4