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

Side Effects of Perindopril

Perindopril shares the adverse effect profile common to all ACE inhibitors, with cough being the most frequent side effect, occurring in approximately 27% of patients, though less than 2% discontinue therapy because of it. 1, 2

Common Adverse Effects

Most Frequent Side Effects

• Cough: Occurs in 26.9% of patients (compared to placebo), representing the most common adverse event and the leading cause of drug discontinuation 3, 1
• Dizziness/Syncope: Reported in 29-33% of patients, significantly higher than placebo 3
• Hypotension: Occurs in 15.9% of patients, particularly during initial dosing or dose escalation 3, 1
• Fatigue: Reported in approximately 7% of patients 3

Gastrointestinal Effects

• Diarrhea, constipation, dry mouth, nausea, vomiting, abdominal pain, and dyspepsia occur in 1-2% of patients 1
• Flatulence and gastroenteritis are reported in approximately 1% of patients 1

Neurological Effects

• Headache, dizziness, and vertigo are common complaints 1
• Migraine, amnesia, and rarely cerebrovascular accidents (0.2%) have been reported 1

Serious Adverse Effects Related to Angiotensin Suppression

Hypotension

• Symptomatic hypotension occurs in 0.3% of uncomplicated hypertensive patients but is more common in volume-depleted patients 1
• Risk is highest during the first few days of therapy, particularly in patients with hypovolemia, recent marked diuresis, or severe hyponatremia (sodium <130 mmol/L) 3
• In heart failure patients, excessive hypotension may lead to oliguria, azotemia, and rarely acute renal failure and death 1
• Management approach: Reduce diuretic doses, liberalize salt intake (if no fluid retention), or stagger timing of other hypotensive agents before initiating perindopril 3

Worsening Renal Function

• Increases in serum creatinine occur in 15-30% of patients with severe heart failure, but only 5-15% with mild to moderate symptoms 3
• Functional renal insufficiency can occur because glomerular filtration becomes critically dependent on angiotensin II-mediated efferent arteriolar vasoconstriction 3
• Risk is highest in patients with bilateral renal artery stenosis, volume depletion, or severe heart failure 3
• Monitoring requirement: Check renal function before initiation, 1-2 weeks after each dose increment, and at 3-6 month intervals 3

Hyperkalemia

• Occurs in 1.4-4.9% of patients receiving perindopril 1
• Risk is markedly enhanced when combined with potassium-sparing diuretics or aldosterone antagonists 3, 4
• Regular monitoring of potassium levels is essential, especially when combining with other agents affecting potassium homeostasis 3

Serious Adverse Effects Related to Kinin Potentiation

Angioedema

• Occurs in 0.1-3.8% of patients treated with perindopril 3, 1
• Can involve face, extremities, lips, tongue, glottis, and/or larynx 1
• Angioedema involving the tongue, glottis, or larynx may be fatal due to airway obstruction 1
• Patients with prior history of angioedema (even unrelated to ACE inhibitors) are at increased risk 1
• Management: Immediately discontinue perindopril; administer subcutaneous epinephrine 1:1000 (0.3-0.5 mL) for laryngeal involvement 1

Intestinal Angioedema

• Presents with abdominal pain (with or without nausea/vomiting) 1
• May occur without prior facial angioedema and with normal C-1 esterase levels 1
• Diagnosed by abdominal CT scan, ultrasound, or at surgery 1
• Symptoms resolve after stopping the ACE inhibitor 1

Other Medically Important Adverse Effects

Hematologic Effects

• Neutropenia/agranulocytosis: Rare in uncomplicated patients but more frequent in those with renal impairment or collagen vascular disease 1
• Leukopenia observed in 0.1% of patients 1
• Small decreases in hemoglobin and hematocrit occur frequently but are rarely clinically significant 1

Hepatic Effects

• Elevations in ALT (1.6%) and AST (0.5%) have been observed 1
• These elevations are generally mild, transient, and resolve after discontinuation 1
• Rare cases of hepatic failure and jaundice (hepatocellular or cholestatic) have been reported with ACE inhibitors 1

Metabolic Effects

• Increases in serum uric acid, triglycerides, and cholesterol when combined with thiazide diuretics 1
• Hyperglycemia reported in 4.1% of patients 3
• Perindopril does not negatively affect glycemic control in diabetic patients 2, 5

Contraindications and Absolute Warnings

Pregnancy

• ACE inhibitors cause fetal and neonatal morbidity and death when administered during pregnancy 1
• Use during second and third trimesters is associated with fetal hypotension, skull hypoplasia, anuria, reversible or irreversible renal failure, and death 1
• Oligohydramnios can lead to fetal limb contractures, craniofacial deformation, and hypoplastic lung development 1
• Discontinue immediately when pregnancy is detected 1

Absolute Contraindications

• Bilateral renal artery stenosis 3
• History of angioedema during previous ACE inhibitor therapy 3, 1

Special Populations and Drug Interactions

Anaphylactoid Reactions

• Life-threatening reactions can occur during desensitization with hymenoptera venom 1
• Reactions reported during dialysis with high-flux membranes 1
• Reactions during low-density lipoprotein apheresis with dextran sulfate absorption 1

Drug Interactions

• Aspirin: May attenuate hemodynamic benefits of ACE inhibitors, though clinical significance remains controversial 3
• Potassium-sparing diuretics: Markedly increase risk of hyperkalemia 3, 4
• Perindopril has no other known clinically significant drug-drug interactions 2

Discontinuation Rates

• Overall discontinuation rate is approximately 12-22% 3, 1
• Most common reasons for discontinuation: cough, drug intolerance, and hypotension 1

Comparative Safety Profile

• Perindopril appears to have lower rates of first-dose hypotension and hyperkalemia compared to other ACE inhibitors 2
• The favorable safety profile extends to elderly patients and those with heart failure or renal disease 2
• No negative effects on lipid profiles in hyperlipidemic patients 2, 5