Renin-angiotensin-aldosterone system inhibitors

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 (RAAS)

• 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 “Renin-angiotensin-aldosterone system” in “Adrenal gland.”

Types of RAAS inhibitors

Angiotensin-converting enzyme inhibitors (ACE inhibitors)

• Drug names: enalapril, lisinopril, ramipril, captopril, benazepril
• Indications
  • Arterial hypertension
  • Diabetes mellitus (type I and type II) with ; ^[1][2]
    • Nephroprotective indications, such as:
      • Arterial hypertension
      • Microalbuminuria and proteinuria (especially ≥ 300 mg/g)
    • Coronary heart disease
  • Heart failure with reduced ejection fraction ^[3]
    • Survival benefit (the exact mechanisms are poorly understood)
    • Any murmur that decreases with amyl nitrite has an etiology that is treatable with ACE inhibitors.
  • History of myocardial infarction ^[4]
  • 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
  • Angioedema: can be tried under close surveillance if no adequate alternative is available ^[5]
  • Non-life-threatening side effects (e.g., dry cough) : commonly used ^[6]

Angiotensin receptor-neprilysin inhibitors (ARNIs)

• Drug names: sacubitril/valsartan
• Indication: Stage C or D HFrEF (preferred initial agent for RAAS inhibition) ^[7]

Direct renin inhibitors

• Drug names: aliskiren
• Indications: arterial hypertension if both ACE inhibitors and ARBs are not tolerated

ACE inhibitors

• Mechanism of action: inhibition of ACE → ↓ conversion of angiotensin I to angiotensin II
• Main effects
  • ↓ Angiotensin II
    • ↓ Vasoconstriction → ↓ blood pressure
    • ↓ Secretion of aldosterone
      • → ↓ Reabsorption of Na⁺ and water → ↓ blood pressure
      • → ↓ Potassium excretion in the collecting duct → ↑ serum levels of potassium (hyperkalemia)
  • Dilation of efferent arteriole → ↑ renal plasma flow → ↓ GFR → ↓ filtration fraction
    • ↑ Renin secretion (due to lack of feedback inhibition) → ↑ angiotensin I
  • ↓ Breakdown of bradykinin; → ↑ production of arachidonic acid metabolites → ↑ vasodilation → ↓ blood pressure
• Other effects
  • ↓ Proteinuria and ↓ progression of proteinuric chronic kidney disease: ↓ intraglomerular hydrostatic pressure attenuates thickening and sclerosis of the GBM
  • ↓ Preload and afterload → ↓ cardiac remodeling; after acute myocardial infarction or in chronic hypertensive disease

ARBs

• Mechanism of action: inhibition of angiotensin II receptor type 1 (AT₁ receptor)
• Main effects
  • ↓ Vasoconstriction → ↓ blood pressure
  • ↓ Secretion of aldosterone
    • → ↓ Reabsorption of Na⁺ and water → ↓ blood pressure
    • → ↓ Potassium excretion in the collecting duct → ↑ serum levels of potassium (hyperkalemia)
  • ↑ Renin secretion (compensatory) → ↑ angiotensin I → ↑ angiotensin II
• Other effects
  • ↓ Proteinuria and ↓ progression of proteinuric kidney disease
  • ↓ Cardiac remodeling after acute myocardial infarction or chronic hypertensive disease
  • No bradykinin elevation (opposed to ACE inhibitors)

ARNIs

• Mechanism of action
  • Sacubitril impairs the breakdown of angiotensin II, substance P, and natriuretic peptides → ↑ natriuresis, diuresis, and vasodilation → ↓ extracellular fluid
  • Combination with an ARB is necessary to block the vasoconstrictive effect of angiotensin II accumulation.

Direct renin inhibitors (DRIs)

• Mechanism of action: direct inhibition of renin → ↓ conversion of angiotensinogen into angiotensin I → ↓ angiotensin I and angiotensin II → ↓ angiotensin II → ↓ vasoconstriction
• Main effects
  • ↓ Blood pressure
  • ↓ Secretion of aldosterone
    • → ↓ Reabsorption of Na⁺ and water → further ↓ blood pressure
    • → ↓ Potassium excretion in the collecting duct → ↑ serum levels of potassium (hyperkalemia)

aLESkiREN: LESS RENin with aliskiren.

ACEIs, ARBs, and DRIs converge on the suppression of aldosterone, which decreases the activity of Na+/K+-ATPase and ROMK channels within the principal cells of the collecting duct. This inhibition impairs renal potassium secretion into the tubular lumen, leading to decreased urinary excretion and elevated serum potassium levels (hyperkalemia).

ACE inhibitors

• Increase in bradykinin concentration, which can lead to:
  • Dry cough (can be treated by discontinuing ACE inhibitor, consider switching to ARB) ^[8][9]
  • Bradykinin-mediated angioedema due to increased vascular permeability and vasodilation
• Hyperkalemia
• ↓ GFR (with ↑ creatinine): can cause acute kidney injury in patients with preexisting renal hypoperfusion (e.g., renal artery stenosis, hypovolemia, heart failure) ^[10]
• Hypotension
• Proteinuria
• Pemphigus vulgaris (unknown mechanism) ^[11]
• Teratogenicity: renal malformations
• Leukopenia
• Rash
• Taste changes

Side effects of CAPTOPRIL: Cough, Angioedema, Pemphigus vulgaris, Teratogenicity, hypOtension, high Potassium, Renal failure, Increased creatinine, Low GFR.

ARBs

• Hyperkalemia
• ↓ GFR (with ↑ creatinine)
• Hypotension
• Teratogenicity
• Leukopenia
• Rash

Unlike ACE inhibitors, ARBs do not increase bradykinin levels and are therefore less likely to cause cough or angioedema, but are teratogenic and share the same renal hemodynamic effects as ACE inhibitors.

ARNIs

ARNIs have the same contraindications as ACEIs.

• Monitor for hypotension, dizziness, or cough.
• Regular laboratory studies for hyperkalemia

Direct renin inhibitors

• Hyperkalemia
• ↓ GFR (with ↑ creatinine)
• Hypotension
• Angioedema
• Teratogenicity
• Rash
• Diarrhea

Acute kidney injury is a potential side effect of all types of RAAS inhibitors, especially in patients with preexisting kidney disease or in combination with NSAIDs.

We list the most important adverse effects. The selection is not exhaustive.

Contraindications for ACE inhibitors and ARBs

• Absolute contraindications
  • Hypersensitivity
  • C1 esterase inhibitor deficiency (due to predisposition to angioedema)
  • Pregnancy: risk of harm to the fetus (e.g., renal impairment, renal malformations, oligohydramnios, placental insufficiency) ^[1]
  • Breastfeeding
• Relative contraindications
  • Aortic stenosis
  • Renal dysfunction, consider altering dose if GFR < 60 mL/min ^[12][13]
  • Bilateral renal artery stenosis or a solitary kidney: GFR is already decreased and further reduction may lead to acute kidney injury.
  • Drug interactions: See “Interactions” below.

Normally, angiotensin II constricts efferent vessels, increasing the GFR. ACE inhibitors antagonize the conversion of angiotensin I to angiotensin II, reducing the GFR.

Contraindications for direct renin inhibitors

• Hypersensitivity
• Pregnancy
• 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 ^[14]

• 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 ^[15][16]

Direct renin inhibitors ^[17]

• P-glycoprotein inhibitors; (e.g., ketoconazole, verapamil; , clarithromycin, erythromycin, amiodarone): ↑ aliskiren level
• ACE inhibitors or ARBs → ↑ hyperkalemia ^[18]

Do not combine direct renin inhibitors with ACE inhibitors or ARBs, especially in patients with diabetes or preexisting kidney disease.

• Starting with low doses (preferably in a controlled setting) is recommended to avoid severe hypotension. ^[13]
• 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.