Perindopril

Perindopril is a long acting angiotensin converting enzyme inhibitor prodrug converted to perindoprilat. It treats hypertension, heart failure and stable coronary artery disease, and lowers cardiovascular events. Two salts with different strengths exist, a common source of dosing confusion.

Classification. Angiotensin converting enzyme inhibitor; prodrug.

Mechanism. Perindoprilat blocks angiotensin converting enzyme, lowering angiotensin II and aldosterone and increasing bradykinin.

Pharmacodynamics. Onset 1 to 2 hours, peak 3 to 6 hours, duration 24 hours. Full effect over about 4 weeks.

Pharmacokinetics. Oral bioavailability about 25% as perindoprilat; food reduces conversion, so take before eating. Terminal half life long (30 to 120 hours) owing to enzyme binding; effective half life 24 hours. Excreted in urine.

Strengths. Perindopril arginine 5 mg equals perindopril erbumine (tert-butylamine) 4 mg; 10 mg arginine equals 8 mg erbumine. Prescribe by the named salt.

Hypertension, adult.

• Start perindopril erbumine 4 mg (arginine 5 mg) once daily before breakfast; 2 mg (arginine 2.5 mg) in older adults, on diuretics, or with kidney impairment.

• Increase after 4 weeks if needed to 8 mg (arginine 10 mg) once daily.

• Maximum 8 mg erbumine (10 mg arginine) daily.

Heart failure with reduced ejection fraction, adult. Start 2 mg erbumine (arginine 2.5 mg) once daily; increase after 2 weeks to 4 mg (arginine 5 mg); maximum 4 mg erbumine (5 mg arginine) daily.

Stable coronary artery disease, adult. 4 mg erbumine (arginine 5 mg) once daily for 2 weeks, then 8 mg (arginine 10 mg) if tolerated.

Secondary prevention after stroke (with a thiazide like diuretic), adult. 2 mg erbumine daily for 2 weeks, then 4 mg daily; add indapamide.

Children. Not established.

Contraindications. Pregnancy; history of angioedema; bilateral renal artery stenosis; hyperkalaemia; concurrent sacubitril with valsartan (36 hour gap); hypotension.

Warnings. Angioedema (higher frequency in patients of African ancestry). Dry cough. First dose hypotension. Hyperkalaemia and decline in kidney function. Sick day rule: hold during dehydrating illness. Neutropenia (rare).

Adverse effects. Cough, dizziness, headache, hypotension, taste disturbance, hyperkalaemia, creatinine rise, angioedema.

Interactions. Potassium supplements, potassium sparing diuretics, trimethoprim: hyperkalaemia. Non steroidal anti-inflammatory drugs: kidney injury. Lithium: toxicity. Diuretics: hypotension. Aliskiren: avoid in diabetes and kidney impairment. Sacubitril: angioedema.

Special groups.

• Pregnancy: contraindicated; stop when pregnancy is confirmed.

• Breastfeeding: avoid; no data.

• Patients of African ancestry: reduced response as monotherapy; angioedema risk higher.

• Older adults: start at 2 mg erbumine.

• Kidney impairment: creatinine clearance 30 to 60 mL/min: 2 mg erbumine (arginine 2.5 mg) daily; 15 to 30 mL/min: 2 mg on alternate days; under 15 mL/min: 2 mg on dialysis days after dialysis.

• Liver impairment: no adjustment; conversion may be reduced.

Formulations. Erbumine tablets 2, 4, 8 mg; arginine tablets 2.5, 5, 10 mg.

Administration. Oral once daily before breakfast. Do not substitute salts without recalculating the dose.

Baseline. Blood pressure, creatinine and eGFR, potassium, pregnancy status, history of angioedema.

Monitoring. Creatinine and potassium 1 to 2 weeks after starting or each dose increase, then every 6 to 12 months. Accept a creatinine rise up to 30%; reduce or stop if over 30% or potassium is over 6.0 mmol/L; review contributors if potassium is over 5.5 mmol/L.

Stopping. Stop for angioedema, pregnancy, intractable cough, or creatinine rise over 30% or potassium over 6.0 mmol/L.

Common prescribing errors. Confusing arginine and erbumine strengths; taking after food; not adjusting the dose in kidney impairment; use in pregnancy.