Aliskiren

Aliskiren is an oral direct renin inhibitor that blocks the first and rate limiting step of the renin angiotensin system. It lowers blood pressure but has no proved outcome benefit and causes harm when combined with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in diabetes or kidney impairment. It is rarely used and is not stocked in many East African markets.

Classification. Direct renin inhibitor.

Mechanism. Binds renin and prevents conversion of angiotensinogen to angiotensin I, lowering plasma renin activity, angiotensin II and aldosterone.

Pharmacodynamics. Onset within 2 hours; full effect over 2 to 4 weeks; duration 24 hours. Plasma renin concentration rises while plasma renin activity falls.

Pharmacokinetics. Bioavailability about 2.5%; a high fat meal cuts exposure by up to 70%. Half life about 24 to 40 hours. A substrate of P-glycoprotein and CYP3A4; excreted mostly unchanged in faeces.

Hypertension, adult.

• Start 150 mg once daily.

• Increase after 2 to 4 weeks to 300 mg once daily if needed.

• Maximum 300 mg daily.

• Use as a second or third line option when other agents are not tolerated; do not combine with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in diabetes or when creatinine clearance is under 60 mL/min.

Children. Not advised under 6 years; aged 6 to 17 years: weight based dosing in specialist care only.

Contraindications. Pregnancy; history of angioedema (including with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker); concurrent angiotensin converting enzyme inhibitor or angiotensin receptor blocker in diabetes or in creatinine clearance under 60 mL/min; concurrent ciclosporin, itraconazole or other strong P-glycoprotein inhibitors; hyperkalaemia.

Warnings. Hypotension, hyperkalaemia and kidney function decline. Angioedema, including airway involvement. Sick day rule: hold during dehydrating illness. Diarrhoea at 300 mg. Excess lowering of blood pressure in volume depleted patients.

Adverse effects. Diarrhoea, hyperkalaemia, creatinine rise, cough, rash, angioedema, dizziness, hypotension.

Interactions. Ciclosporin and itraconazole: markedly raise aliskiren (avoid). Ketoconazole, verapamil and other P-glycoprotein inhibitors: raise levels. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers: hyperkalaemia, kidney injury, hypotension. Potassium sparing diuretics and non steroidal anti-inflammatory drugs: hyperkalaemia and kidney injury. Atorvastatin: modest rise in exposure. Furosemide: lowered furosemide levels. High fat food reduces absorption.

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: no adjustment; monitor.

• Kidney impairment: severe (creatinine clearance under 30 mL/min): use with caution; avoid with other renin angiotensin agents.

• Liver impairment: no adjustment.

Formulations. Tablets 150 and 300 mg; combinations with hydrochlorothiazide or amlodipine in some markets.

Administration. Oral once daily, taken consistently with or without a light meal; avoid high fat meals and grapefruit juice.

Baseline. Blood pressure, creatinine and eGFR, potassium, pregnancy status, drug history for interacting agents.

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. Blood pressure and bowel habit.

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

Common prescribing errors. Combining with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in diabetes or kidney impairment; giving with ciclosporin or itraconazole; taking with a high fat meal; use in pregnancy.