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Tuesday, July 29, 2025

Perindopril


Generic Name: Perindopril
Active Form: Perindopril erbumine (perindopril tert-butylamine)
Brand Names: Coversyl, Aceon (US), Prestarium, Arvindil, Perindo, Prexanil


Drug Class: Angiotensin-Converting Enzyme (ACE) Inhibitor
Pharmaceutical Category: Antihypertensive agent; Cardiovascular drug
Formulations: Oral tablets (2 mg, 4 mg, 8 mg), combination products with indapamide or amlodipine
Route of Administration: Oral

1. Pharmacological Classification

Perindopril is a long-acting angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension, heart failure, and prevention of cardiovascular events in high-risk patients. As a prodrug, it is converted in the liver to its active form perindoprilat, which binds to and inhibits the ACE enzyme, leading to vasodilation and cardiovascular protection.

2. Mechanism of Action

Perindopril inhibits angiotensin-converting enzyme (ACE), which catalyzes the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. The inhibition results in:

  • Vasodilation (decreased peripheral vascular resistance)

  • Reduction in aldosterone secretion, decreasing sodium and water retention

  • Improved cardiac output and renal perfusion

  • Enhanced bradykinin activity (due to reduced breakdown), which further promotes vasodilation and may contribute to cough

The net effect includes lower blood pressure, reduced afterload and preload, and cardiovascular remodeling inhibition.

3. Therapeutic Indications

A. Approved Uses

  • Hypertension: Treatment of essential hypertension

  • Stable coronary artery disease: To reduce the risk of myocardial infarction or cardiac death

  • Heart failure: Especially post-myocardial infarction or with reduced ejection fraction (HFrEF)

  • Post-stroke secondary prevention (especially in combination with indapamide)

B. Combination Formulations

  • Perindopril + Indapamide: For more effective blood pressure control (e.g., Coversyl Plus)

  • Perindopril + Amlodipine: Combines vasodilatory effects of ACE inhibitor and calcium channel blocker

4. Dosage and Administration

Adults (Hypertension)

  • Starting dose: 4 mg once daily in the morning

  • May be increased to 8 mg once daily after 2–4 weeks, depending on blood pressure response

Heart Failure

  • Initial dose: 2 mg once daily

  • Titrate slowly to target maintenance dose: 4 mg once or twice daily

Stable Coronary Artery Disease

  • Start with 4 mg once daily for 2 weeks, then increase to 8 mg once daily

Elderly (≥65 years)

  • Initiate at 2 mg once daily; titrate cautiously

Pediatric Use

  • Not recommended; safety and efficacy have not been established

5. Pharmacokinetics

  • Absorption: Rapid after oral administration; bioavailability ~65–75%

  • Conversion: Hepatic conversion to active metabolite perindoprilat

  • Peak plasma (perindoprilat): 3–6 hours

  • Protein binding: Perindoprilat ~10–20% (mostly tissue-bound)

  • Half-life: Terminal half-life of perindoprilat is ~30–120 hours (due to high tissue binding)

  • Elimination: Primarily renal excretion of perindoprilat and its metabolites

  • Dose adjustment: Required in renal impairment

6. Contraindications

  • History of angioedema associated with previous ACE inhibitor therapy

  • Hereditary or idiopathic angioedema

  • Pregnancy (especially 2nd and 3rd trimesters)

  • Severe renal impairment (eGFR <30 mL/min/1.73 m²) unless under specialist supervision

  • Concomitant use with aliskiren in diabetic patients or patients with renal impairment

  • Hypersensitivity to perindopril or other ACE inhibitors

7. Warnings and Precautions

A. Angioedema

  • Potentially life-threatening swelling of the lips, tongue, face, or airway

  • Higher risk in Black patients

B. Hypotension

  • Especially in patients who are volume-depleted, on diuretics, or have heart failure

  • Start with low doses and monitor

C. Renal Function Deterioration

  • Can cause acute renal failure, especially in bilateral renal artery stenosis or pre-existing kidney disease

  • Monitor serum creatinine and eGFR regularly

D. Hyperkalemia

  • Inhibits aldosterone → potassium retention

  • Monitor serum potassium, especially when used with potassium-sparing diuretics or potassium supplements

E. Dry Cough

  • Non-productive, persistent cough due to bradykinin accumulation

  • Typically resolves upon discontinuation

F. Hepatotoxicity

  • Rare cases of cholestatic jaundice and hepatitis

G. Neutropenia/Agranulocytosis

  • Rare but serious, especially in immunocompromised or renal-impaired patients

8. Adverse Effects

Common (≥1%)

  • Dizziness

  • Headache

  • Fatigue

  • Dry cough

  • Hypotension

  • Nausea

  • Abdominal pain

  • Skin rash

Less Common (0.1–1%)

  • Hyperkalemia

  • Renal impairment

  • Depression

  • Palpitations

  • Muscle cramps

Rare (<0.1%)

  • Angioedema

  • Hepatitis

  • Blood dyscrasias (neutropenia, agranulocytosis)

  • Stevens–Johnson syndrome

  • Anaphylactoid reactions

9. Drug Interactions

Potassium-sparing diuretics (e.g., spironolactone, amiloride) and supplements

  • ↑ Risk of hyperkalemia

  • Monitor serum potassium regularly

Diuretics (especially loop and thiazide)

  • ↑ Risk of hypotension at therapy initiation

  • Consider holding diuretic temporarily when starting perindopril

NSAIDs

  • May blunt antihypertensive effects and ↑ risk of renal dysfunction

Lithium

  • ACE inhibitors ↓ renal clearance of lithium → toxicity

  • Avoid or monitor lithium levels closely

Antidiabetic drugs (insulin, sulfonylureas)

  • May ↑ risk of hypoglycemia (enhanced insulin sensitivity)

Other antihypertensives

  • Additive hypotensive effect, especially with ARBs, diuretics, or beta-blockers

Dual blockade (ACEi + ARB or aliskiren)

  • Not recommended due to ↑ risk of hyperkalemia, hypotension, and renal failure

10. Pregnancy and Lactation

Pregnancy

  • Contraindicated during second and third trimesters

  • Risk of fetal renal dysfunction, oligohydramnios, skull hypoplasia, intrauterine death

  • Discontinue immediately if pregnancy is confirmed

Lactation

  • Limited data; avoid if possible

  • Alternative agents preferred in breastfeeding mothers

11. Monitoring Parameters

  • Blood pressure and heart rate

  • Serum creatinine and eGFR (baseline and periodically)

  • Serum potassium

  • Signs of angioedema or hypersensitivity

  • Liver enzymes (if symptoms suggest hepatic dysfunction)

12. Formulations and Brand Availability

Tablets:

  • 2 mg, 4 mg, 8 mg (perindopril erbumine or tert-butylamine)

Combination Products:

  • Perindopril + Indapamide (e.g., Coversyl Plus, Noliprel)

  • Perindopril + Amlodipine (e.g., Coveram)

  • Generic and branded options available globally

13. Comparative Notes and Clinical Pearls

  • Long-acting ACE inhibitor with once-daily dosing and good 24-hour BP control

  • Perindopril + indapamide combination demonstrated stroke and CV risk reduction in the PROGRESS study

  • Well tolerated; cough incidence lower than some other ACE inhibitors (though still present)

  • Suitable for use in elderly, particularly when cardiovascular protection is a primary concern

  • Preferred over short-acting ACE inhibitors (like captopril) in long-term management



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