Renin-angiotensin-aldosterone system (RAAS) inhibitors are a group of drugs that act by inhibiting the renin-angiotensin-aldosterone system (RAAS) and include angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin-receptor blockers (ARBs), and direct renin inhibitors. ACE inhibitors and ARBs are commonly used in the treatment of patients with hypertension, heart failure with reduced ejection fraction, and certain types of chronic kidney disease, as well as patients who have had a myocardial infarction. They are particularly important in the treatment of hypertensive diabetic patients, as they prevent the development of diabetic nephropathy. A common side effect of ACE inhibitors is a bradykinin-induced cough, which may necessitate switching to an alternative therapy (e.g., ARBs), while angioedema and hyperkalemia may occur with both ARBs and ACE inhibitor use. Direct renin inhibitors may be considered in hypertensive patients if ACE inhibitors or ARBs are not well tolerated; however, they should never be used in combination with other RAAS inhibitors.
The renin-angiotensin-aldosterone system ( )
- Drops in blood pressure reduce renal perfusion.
- If the pressure in the renal artery falls by more than 10–15 mmHg, proteolytic renin is released from the juxtaglomerular apparatus → renin converts angiotensinogen to angiotensin I → ACE cleaves C-terminal peptides on angiotensin I, converting it to angiotensin II → increases the blood pressure in two ways: vasoconstriction and stimulation of the release of aldosterone, which increases the retention of water and sodium
- For more information, see “ ” in “ .”
Types of RAAS inhibitors
Angiotensin-converting enzyme inhibitors (ACE inhibitors)
- Drug names: enalapril, lisinopril, ramipril, captopril, benazepril
- Diabetes mellitus (type I and type II) with ; 
- History of myocardial infarction 
- Nondiabetic chronic kidney disease with proteinuria
- Scleroderma-associated hypertensive crisis (even if creatinine is elevated)
Angiotensin-receptor blocker (ARBs, sartans)
- Drug names: valsartan, candesartan, losartan, irbesartan
- Indications: same as ACE inhibitors, mostly used as second-line treatment if ACE inhibitors are not tolerated
Angiotensin receptor-neprilysin inhibitors (ARNIs)
- Drug names: sacubitril/valsartan
- Indication: Stage C or D HFrEF (preferred initial agent for RAAS inhibition) 
Direct renin inhibitors
- Mechanism of action: inhibition of ACE → ↓ conversion of angiotensin I to angiotensin II
- ↓ Angiotensin II
- ↓ Breakdown of bradykinin →; ↑ production of arachidonic acid metabolites → ↑ vasodilation → ↓ blood pressure
- Other effects
- Mechanism of action: inhibition of angiotensin II receptor type 1 (AT1 receptor)
- Main effects
- Other effects
- Mechanism of action
- Mechanism of action: direct inhibition of renin → ↓ conversion of angiotensinogen into angiotensin I → ↓ angiotensin I and angiotensin II → ↓ angiotensin II → ↓ vasoconstriction
- ↓ Blood pressure
- ↓ Secretion of aldosterone → ↓ reabsorption of Na+ and water → further ↓ blood pressure
- Increase in bradykinin concentration, which can lead to:
- ↓ GFR (with ↑ creatinine): can cause acute kidney injury in patients with preexisting renal hypoperfusion (e.g., renal artery stenosis, hypovolemia, heart failure) 
- Pemphigus vulgaris (unknown mechanism) 
- Teratogenicity: renal malformations
- Taste changes
We list the most important adverse effects. The selection is not exhaustive.
Contraindications for ACE inhibitors and ARBs
- Absolute contraindications
- Relative contraindications
Contraindications for direct renin inhibitors
- Current treatment with ACE inhibitors or ARBs
- Drug interactions: See “Interactions” below.
We list the most important contraindications. The selection is not exhaustive.
ACE inhibitors and ARBs 
- Other antihypertensive drugs → ↑ hypotensive effect
- NSAIDs → ↓ antihypertensive effect
- Potassium-sparing diuretics; or other drugs that increase potassium level: ↑ hyperkalemia
- ↑ Level of lithium due to ↓ renal elimination
- Allopurinol: ↑ risk of immunological reactions or leukopenia 
- P-glycoprotein inhibitors; (e.g., ketoconazole, verapamil; , clarithromycin, erythromycin, amiodarone): ↑ aliskiren level
- ACE inhibitors or ARBs → ↑ hyperkalemia 
- Starting with low doses (preferably in a controlled setting) is recommended to avoid severe hypotension. 
- Combine ACE inhibitors or ARBs with thiazide diuretics to offset the risks of hyperkalemia and hypokalemia.
- When starting an ACE inhibitor or an ARB, monitor blood pressure, potassium, and creatinine.