What are the side effects of lisinopril?

Side Effects of Lisinopril

Lisinopril is generally well tolerated, with the most common side effects being cough (occurring in approximately 2.5% more patients than placebo), dizziness (3.5% more than placebo), and headache (3.8% more than placebo), while serious adverse events like angioedema, hyperkalemia, and renal dysfunction require vigilant monitoring but occur less frequently. 1

Common Side Effects (Occurring in ≥2% of Patients)

Respiratory and Neurological

• Dry cough is the most characteristic ACE inhibitor side effect, occurring in approximately 2.5% more patients on lisinopril than placebo, caused by bradykinin accumulation due to ACE inhibition 1
• Dizziness affects 3.5% more patients than placebo, typically related to blood pressure lowering effects and most common during initial dose titration 1
• Headache occurs in 3.8% more patients than placebo and usually resolves with continued therapy 1

Cardiovascular

• Hypotension is more common in heart failure patients (3.8% more than placebo) and in post-myocardial infarction patients (5.3% more than placebo), particularly in volume-depleted patients or those on concurrent diuretics 1
• Chest pain occurs in 2.1% more heart failure patients on lisinopril than placebo 1

Gastrointestinal

• Diarrhea occurs in approximately 1% or more of patients, though the exact differential versus placebo is not specified 1
• Constipation, flatulence, and dry mouth each occur in ≥1% of patients 1

General

• Fatigue and asthenia (weakness) occur in ≥1% of patients and may be related to blood pressure lowering 1

Serious Adverse Events Requiring Immediate Action

Angioedema (Life-Threatening)

• Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx can occur at any time during treatment and has resulted in fatal reactions 1
• Black patients have a higher rate of angioedema with ACE inhibitors compared to non-Black patients 1
• Patients with tongue, glottis, or laryngeal involvement are at high risk for airway obstruction, especially those with prior airway surgery 1
• Intestinal angioedema presents with abdominal pain (with or without nausea/vomiting), may occur without facial angioedema, and requires CT scan or ultrasound for diagnosis 1
• Lisinopril must be discontinued immediately if angioedema occurs, and patients with prior angioedema (even unrelated to ACE inhibitors) are at increased risk 2, 1

Renal Complications

• Renal dysfunction occurred in 1.3% more post-MI patients on lisinopril than controls 1
• Acute renal failure can develop, particularly in patients with renal artery stenosis, chronic kidney disease, severe heart failure, post-MI, or volume depletion whose renal function depends on the renin-angiotensin system 1
• Minor increases in blood urea nitrogen and serum creatinine (reversible upon discontinuation) occur in approximately 2% of hypertensive patients, more commonly with concurrent diuretics or renal artery stenosis 1
• Renal function and serum potassium should be assessed within 1-2 weeks of initiation and periodically thereafter, especially in high-risk patients 2

Electrolyte Abnormalities

• Hyperkalemia (serum potassium >5.7 mEq/L) occurred in 2.2% of hypertensive patients and 4.8% of heart failure patients on lisinopril 1
• Risk is increased in patients with chronic kidney disease, diabetes, those taking potassium supplements, potassium-sparing diuretics, or NSAIDs 3, 4
• Unlike thiazide diuretics which cause potassium depletion, lisinopril causes potassium retention through renin-angiotensin-aldosterone system inhibition 4

Less Common but Clinically Important Side Effects (≥1%)

Hematologic

• Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia, and thrombocytopenia have been reported 1

Dermatologic

• Urticaria, alopecia, photosensitivity, erythema, flushing, diaphoresis, and pruritus occur in ≥1% of patients 1
• Rare but serious skin reactions include toxic epidermal necrolysis, Stevens-Johnson syndrome, and cutaneous pseudolymphoma 1

Metabolic and Endocrine

• Gout can occur, likely related to changes in uric acid handling 1
• Diabetes mellitus and inappropriate antidiuretic hormone secretion have been reported 1

Sensory

• Visual disturbances including visual loss, diplopia, blurred vision, and photophobia can occur 1
• Taste disturbances, olfactory disturbance, and tinnitus affect ≥1% of patients 1

Genitourinary

• Impotence occurs in ≥1% of male patients 1

Autoimmune-Like Syndrome

• A symptom complex may include positive ANA, elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, leukocytosis, paresthesia, and vertigo 1
• Rash, photosensitivity, or other dermatological manifestations may occur alone or combined with these symptoms 1

Special Populations and Precautions

Pregnancy

• Lisinopril is Pregnancy Category D and causes fetal toxicity when used during the second and third trimesters 1
• Use reduces fetal renal function and increases fetal/neonatal morbidity and death, potentially causing oligohydramnios, fetal lung hypoplasia, skeletal deformations, skull hypoplasia, anuria, hypotension, renal failure, and death 1
• Discontinue immediately when pregnancy is detected 1

Dialysis and Desensitization

• Life-threatening anaphylactoid reactions have occurred in patients dialyzed with high-flux membranes while on ACE inhibitors; dialysis must be stopped immediately if this occurs 1
• Anaphylactoid reactions during hymenoptera venom desensitization have been reported; antihistamines do not relieve symptoms 1

Renal Impairment

• Significant accumulation occurs in patients with severe renal impairment (creatinine clearance ≤30 mL/min), requiring dose adjustment 5
• Lisinopril is excreted unchanged in the urine, and steady state is achieved in 2-3 days in patients with normal renal function 5

Discontinuation Rates

• In hypertension trials, 5.7% of patients discontinued lisinopril due to adverse reactions 1
• In heart failure trials, 11% discontinued over up to four years, with 8.1% discontinuing in 12-week controlled studies versus 7.7% on placebo 1
• In the ATLAS trial comparing high-dose (32.5-35 mg) versus low-dose (2.5-5 mg) lisinopril in heart failure, discontinuation rates were similar (17-18%) despite higher incidence of hypotension and renal dysfunction with high doses 3, 1

Monitoring Recommendations

• Check serum potassium and creatinine within 1-2 weeks of initiation and periodically thereafter, especially in patients with pre-existing hypotension, hyponatremia, diabetes, azotemia, or those taking potassium supplements 2
• Monitor fluid status carefully, as fluid retention can blunt therapeutic effects and fluid depletion can potentiate adverse effects 2
• Initiate treatment at low doses followed by gradual increments if lower doses have been well tolerated 2

Comparative Tolerability

• Lisinopril's tolerability profile is typical of ACE inhibitors and appears similar in diabetic and non-diabetic individuals 6
• The drug does not produce hypokalemia, hyperglycemia, hyperuricemia, or hypercholesterolemia unlike some other antihypertensive classes 5
• In elderly patients, lisinopril is well tolerated, though there is a tendency for more elderly than younger patients to discontinue treatment, not clearly related to adverse event incidence 7

Drug Interactions Affecting Side Effects

• Concurrent diuretics increase the risk of hypotension and renal dysfunction 1
• NSAIDs can reduce the antihypertensive effect and increase hyperkalemia risk 3
• Lithium toxicity can occur due to reduced renal clearance 7