Ramipril

Ramipril is a long acting angiotensin converting enzyme inhibitor prodrug converted in the liver to ramiprilat. It reduces cardiovascular events in high risk patients, treats hypertension and heart failure, and slows diabetic kidney disease. It is widely available in East Africa.

Classification. Angiotensin converting enzyme inhibitor; prodrug.

Mechanism. Ramiprilat 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 blood pressure effect over 3 to 4 weeks.

Pharmacokinetics. Oral absorption about 55 to 65%. Ramiprilat terminal half life exceeds 50 hours owing to enzyme binding; effective half life 13 to 17 hours. Excreted in urine (about 60%) and faeces.

Hypertension, adult.

• Start 2.5 mg once daily (1.25 mg if on a diuretic, older, or hepatic impairment).

• Increase after 2 to 4 weeks to 5 mg, then 10 mg once daily.

• Usual maintenance 2.5 to 5 mg; maximum 10 mg daily.

Cardiovascular risk reduction in high risk patients (established vascular disease or diabetes with another risk factor), adult. 2.5 mg once daily for 1 week, 5 mg once daily for 3 weeks, then 10 mg once daily.

Heart failure with reduced ejection fraction, adult. Start 1.25 mg once daily; double the dose every 1 to 2 weeks; target 10 mg daily (5 mg twice daily); maximum 10 mg daily.

After myocardial infarction with signs of heart failure (start 2 to 9 days after), adult. 2.5 mg twice daily; after 2 days, 5 mg twice daily; reduce to 1.25 mg twice daily if 2.5 mg is not tolerated.

Non diabetic and diabetic kidney disease with proteinuria, adult. 1.25 mg daily, titrated to a maximum 5 mg daily.

Children. Not established; specialist use.

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

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

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

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

Special groups.

• Pregnancy: contraindicated; stop when pregnancy is confirmed.

• Breastfeeding: avoid; limited data.

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

• Older adults: start at 1.25 mg.

• Kidney impairment: creatinine clearance 30 to 60 mL/min: maximum 5 mg daily; under 30 mL/min: start 1.25 mg, maximum 5 mg daily.

• Liver impairment: start 1.25 mg; maximum 2.5 mg daily.

Formulations. Capsules and tablets 1.25, 2.5, 5, 10 mg; oral solution in some markets.

Administration. Oral once daily; capsules may be opened and contents mixed with water or apple sauce; do not chew.

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. Skipping the stepped titration in risk reduction; exceeding 5 mg in moderate kidney impairment; use in pregnancy; omitting potassium and creatinine checks.