Ramipril

Neil Turner

WHO essential drug

Mechanism of Action:

An angiotensin-converting enzyme (ACE) inhibitor. It is a prodrug that is metabolised to the active agent Ramiprilat, mostly in the liver, but also in kidney.

Indications:

  • Hypertension
  • Heart failure
  • Prophylaxis after myocardial infarction
  • Proteinuric renal disease, including diabetic nephropathy
  • Microalbuminuria caused by diabetes

The enzyme ACE is part of the renin angiotensin aldosterone system (RAAS). Circulating angiotensinogen is converted to angiotensin I [ATI] by the enzyme renin. ACE is responsible for the conversion of ATI to ATII. ATII is a potent vasoconstrictor, and AT III, a metabolite of ATII, stimulates aldosterone secretion. Aldosterone-mediated retention of salt and water leads to increased extracellular fluid volume and subsequently raises blood pressure and increases cardiac output. Lisinopril competes with angiotensin ATI for binding to ACE. Conversion of ATI to ATII is thus prevented and the effects of RAAS diminished.

Learning materials:

Details:

Alternative drug name
Not specified
Effects
Decreases angiotensin II production and so reduces effects on vasoconstriction and aldosterone release. This reduces arterial blood pressure. As well as reducing ‘afterload’ also venodilates and so reduces venous return (‘preload’) making it an effective agent in chronic heart failure.
Adverse actions
Persistent non-productive cough (~1 in 10 patients) which resolves with drug discontinuation, renal impairment (especially in patients with bilateral renal artery stenosis or impaired renal function), hypotension, hyperkalaemia (decreased aldosterone leading to increased potassium blood levels). Rash (uncommon).

The cough is the result of bradykinin accumulation in the lungs which acts as an irritant (ACE inhibitors prevent the breakdown of bradykinin). This is also an important mechanism in a rare but serious problem of angioedema (1 in 1000).

Renal impairment is attributed to the disruption of homeostatic mechanisms (e.g. renal blood flow) controlled by ATII which serves to support renal blood flow in circumstances such as hypotension or dehydration. Risk of severe drop in blood pressure with the first dose of ACE inhibitors (first dose hypotension) is mostly seen in those who are volume-deplete, usually through being on diuretics, but it can also be seen in those who have RAAS greatly upregulated for other reasons (e.g. renal artery stenosis).

ACE inhibitors are contraindicated in pregnancy, at least in mid-pregnancy, as they cause oligohydramnios and may cause other severe abnormalities if exposure in mid-pregnancy.

Rare but severe allergic reaction can occur affecting the bowel and secondarily causing abdominal pain. This “anaphylactic” reaction is very rare but requires immediate attention.
Dose
Usually once daily administration in the range 2.5 to 10 mg). Twice daily dosing is sometimes recommended in heart failure. Doses are usually doubled at intervals of 1-4 weeks for outpatients. Its half life is >24h after multiple doses at 2.5mg daily; 15h at 5-10mg daily.

Lower doses are recommended in patients with low GFR. (EMC on Ramipril)
Interactions
Renal impairment with other drugs affecting renal blood flow e.g. NSAIDs, diuretics. Hypotension with other antihypertensives. Hyperkalaemia with other drugs tending to preserve potassium e.g. potassium sparing diuretics such as spironolactone.
Contraindications
Symptomatically very low blood presssure.
Comments
Other ACE inhibitors include enalapril, lisinopril, perindopril, captopril etc. They vary in their pharmacokinetics but all work in much the same way. Angiotensin receptor blockers such as Losartan have a similar clinical profile to ACE inhibitors.

Not directly related, but of interest for treatment of pulmonary hypertension: ET-1 (endothelin-1) is a potent vasoconstrictor acting via ETA receptors (plus weak dilator action via ETB receptors) and its effects can be antagonized by bosentan, which is slightly more effective at blocking ETA receptors in comparison with ETB. The antagonist is used in treating pulmonary hypertension.
Contributors
Added by ANT Mar 2017 revised 2021

Drug specifics

Alternative drug name not specified
Effects Decreases angiotensin II production and so reduces effects on vasoconstriction and aldosterone release. This reduces arterial blood pressure. As well as reducing ‘afterload’ also venodilates and so reduces venous return (‘preload’) making it an effective agent in chronic heart failure.
Adverse actions

Persistent non-productive cough (~1 in 10 patients) which resolves with drug discontinuation, renal impairment (especially in patients with bilateral renal artery stenosis or impaired renal function), hypotension, hyperkalaemia (decreased aldosterone leading to increased potassium blood levels). Rash (uncommon).

The cough is the result of bradykinin accumulation in the lungs which acts as an irritant (ACE inhibitors prevent the breakdown of bradykinin). This is also an important mechanism in a rare but serious problem of angioedema (1 in 1000).

Renal impairment is attributed to the disruption of homeostatic mechanisms (e.g. renal blood flow) controlled by ATII which serves to support renal blood flow in circumstances such as hypotension or dehydration. Risk of severe drop in blood pressure with the first dose of ACE inhibitors (first dose hypotension) is mostly seen in those who are volume-deplete, usually through being on diuretics, but it can also be seen in those who have RAAS greatly upregulated for other reasons (e.g. renal artery stenosis).

ACE inhibitors are contraindicated in pregnancy, at least in mid-pregnancy, as they cause oligohydramnios and may cause other severe abnormalities if exposure in mid-pregnancy.

Rare but severe allergic reaction can occur affecting the bowel and secondarily causing abdominal pain. This "anaphylactic" reaction is very rare but requires immediate attention.
Dose

Usually once daily administration in the range 2.5mg to 10mg). Twice daily dosing is sometimes recommended in heart failure. Doses are usually doubled at intervals of 1-4 weeks for outpatients. Its half life is >24h after multiple doses at 2.5mg daily; 15h at 5-10mg daily.

Lower doses are recommended in patients with low GFR. (EMC on Ramipril)
Interactions Renal impairment with other drugs affecting renal blood flow e.g. NSAIDs, diuretics. Hypotension with other antihypertensives. Hyperkalaemia with other drugs tending to preserve potassium e.g. potassium sparing diuretics such as spironolactone.
Contraindications not specified
Comments

Other ACE inhibitors include enalapril, lisinopril, perindopril, captopril etc. They vary in their pharmacokinetics but all work in much the same way. Angiotensin receptor blockers such as Losartan have a similar clinical profile to ACE inhibitors.

Not directly related, but of interest for treatment of pulmonary hypertension: ET-1 (endothelin-1) is a potent vasoconstrictor acting via ETA receptors (plus weak dilator action via ETB receptors) and its effects can be antagonized by bosentan, which is slightly more effective at blocking ETA receptors in comparison with ETB. The antagonist is used in treating pulmonary hypertension.

Contributors Added by ANT Mar 2017