ACE inhibitor (renin-angiotensin axis)
Ramipril is a medicine for high blood pressure and heart failure. It belongs to the ACE-inhibitor class and helps the heart and blood vessels work with less effort. It can cause a dry cough and, rarely, swelling of the face (angioedema).
Also known as: Tritace
Dual RAAS blockade (ACE+ARB) with risk of hypotension and renal injury.
Combining an ARB (valsartan) with an ACE inhibitor (ramipril) blocks the RAAS at two steps, adding the risk of hyperkalaemia, hypotension and renal function deterioration. The valsartan label states that "Dual inhibition of the RAS" increases the "risk of renal impairment, hypotension, and hyperkalemia"; the ramipril label documents "Dual Blockade of the Renin-Angiotensin System" among the warnings and "Agents Increasing Serum Potassium" in interactions, and the risk is higher in patients with renal impairment, diabetes or volume depletion. The ONTARGET trial with telmisartan+ramipril showed more renal adverse events without mortality benefit. Avoid in most patients; if absolutely necessary (refractory HF), monitor BP, creatinine and potassium 1–2 weeks after initiation or dose adjustment and reduce the doses of both.
Valsartan + ramipril: dual RAAS blockade — higher risk of hypotension, hyperkalaemia and renal impairment. Avoid; monitor BP, K+ and creatinine if unavoidable.
Enhanced blockade lowers intraglomerular pressure, impairing renal function and raising potassium.
Creatinine, diuresis, potassium.
Hypotension or renal worsening.
Avoid unless proven benefit; monitor renal function.
DailyMed (FDA) — approved Ramipril label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3806abdc-6aec-4252-bd79-e2c115b849aa ; approved Valsartan label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a8af3d9-4053-4233-82a7-e8c7bc9e302f — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
ACE inhibitor plus potassium-sparing diuretic raises hyperkalaemia risk.
Combining an ACE inhibitor (ramipril) with a potassium-sparing diuretic (spironolactone) reduces potassium excretion through two pathways: ramipril lowers aldosterone production and spironolactone blocks the aldosterone receptor in the distal tubule. The result is potassium retention, clinically relevant especially in patients with reduced renal function, diabetes or advanced age. This combination is common in heart failure with reduced ejection fraction, where the benefit is proven — what is required is surveillance: potassium and creatinine about 1 week after starting or adjusting, and reassessment if renal function worsens. Severe hyperkalaemia presents with muscle weakness, paraesthesias and arrhythmias and requires immediate correction.
ACE inhibitor + aldosterone antagonist: additive potassium retention, with a hyperkalaemia risk, especially with reduced GFR, diabetes or advanced age. Monitor potassium and creatinine.
Ramipril lowers aldosterone and spironolactone retains potassium; the effect is additive.
Potassium, creatinine.
Hyperkalaemia (weakness, arrhythmia).
Monitor potassium and renal function; avoid in renal impairment.
DailyMed (FDA) — approved Ramipril label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3806abdc-6aec-4252-bd79-e2c115b849aa ; approved Spironolactone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57d1c333-c229-54aa-e063-6394a90a84ce — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
First-dose ACE-i in a patient on an active diuretic may cause hypotension.
Ramipril (ACE inhibitor) can cause symptomatic hypotension, especially after the first dose, and the risk is higher in patients with volume and/or sodium depletion from prolonged diuretic therapy (such as furosemide); the ramipril label recommends correcting volume/sodium depletion before starting the ACE inhibitor. The combination can also raise serum creatinine (especially in patients with pre-existing renal impairment or renal artery stenosis), possibly requiring dose reduction of the ACE inhibitor and/or the diuretic. Start ramipril at the lowest dose, preferably at bedtime or with the patient supine, monitor blood pressure in the first hours after the first dose, and check creatinine and potassium in the first weeks.
Furosemide + ramipril: risk of symptomatic first-dose hypotension (diuretic-induced volume depletion) and renal deterioration. Monitor blood pressure, creatinine and potassium.
Volume depletion by the diuretic amplifies first-dose ACE-i hypotension.
Blood pressure, presyncope symptoms.
Symptomatic hypotension or syncope on first dose.
Adjust the diuretic before starting the ACE-i and check blood pressure.
DailyMed (FDA) — approved Ramipril label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3806abdc-6aec-4252-bd79-e2c115b849aa ; approved Furosemide label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6d9caaab-d874-4cf1-b9fe-408452a18998 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Ramipril reduces potassium excretion; potassium-rich foods or potassium-containing salt substitutes may cause hyperkalaemia, especially with reduced renal function.
Avoid potassium-containing salt substitutes; usual dietary potassium intake is not problematic.
EMC-UK (MHRA) — approved Ramipril SmPC: https://www.medicines.org.uk/emc/product/8067/smpc
Ramipril is contraindicated in previous ACE-inhibitor-associated angioedema or hereditary/idiopathic angioedema because of the risk of severe recurrence.
Do not use in patients with a history of angioedema; use an alternative class.
EMC-UK (MHRA) — approved Ramipril SmPC: https://www.medicines.org.uk/emc/product/8067/smpc
Ramipril is contraindicated in bilateral renal artery stenosis (or stenosis in a single functioning kidney) because of the risk of acute renal failure.
Do not use; assess renal function and the cause of hypertension before starting an ACE inhibitor.
EMC-UK (MHRA) — approved Ramipril SmPC: https://www.medicines.org.uk/emc/product/8067/smpc
ACE inhibitors are contraindicated in pregnancy: they may cause fetal renal injury, oligohydramnios and skull hypoplasia, especially in the 2nd and 3rd trimesters.
Do not start in pregnancy; if pregnancy is detected, stop ramipril immediately and switch to appropriate alternative therapy.
Not recommended during breastfeeding; prefer an alternative with an established safety profile.
Women of childbearing age must use effective contraception during treatment.
EMC-UK (MHRA) — approved Ramipril SmPC: https://www.medicines.org.uk/emc/product/8067/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Single doses of 2.5 to 20 mg produce about 60 to 80% inhibition of angiotensin-converting enzyme (ACE) at 4 hours and 40 to 60% at 24 hours. With multiple doses of 2 mg or more, plasma ACE activity falls by more than 90% at 4 hours, with over 80% inhibition remaining at 24 hours.
Ramipril is a prodrug; ramiprilat, its active metabolite, inhibits ACE (peptidyl dipeptidase), reducing the conversion of angiotensin I to angiotensin II and aldosterone secretion, with decreased vasopressor activity. Since ACE is identical to kininase, inhibition may increase bradykinin, contributing to the therapeutic effect.
After oral administration, the plasma peak of ramipril is reached within about 1 hour; the extent of absorption is at least 50 to 60%. Food reduces the rate but not the extent of absorption. Ramiprilat peaks 2 to 4 hours after dosing. Plasma protein binding is about 73% (ramipril) and 56% (ramiprilat).
Almost completely metabolised: cleavage of the ester group (mainly in the liver) converts it to ramiprilat (about 6 times more active), and inactive metabolites are formed (diketopiperazine and glucuronides). Absolute bioavailability is 28% (ramipril) and 44% (ramiprilat). About 60% of the dose is eliminated in urine and 40% in faeces.
Ramiprilat has an apparent elimination phase with a half-life of 9 to 18 hours and a prolonged terminal phase (over 50 hours) related to the binding/dissociation of the ACE complex. With multiple 5 to 10 mg doses, the half-life within the therapeutic range is 13 to 17 hours.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
