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 (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, certain types of chronic kidney disease, and patients who have suffered 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 in 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 mm Hg → 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: (1) vasoconstriction and (2) stimulation of the release of aldosterone, which increases the retention of water and sodium

Types of RAAS inhibitors

	Drug names	Indications
ACE inhibitors	Enalapril, lisinopril, ramipril, captopril, benazepril	Arterial hypertension Diabetes mellitus (type I and type II) with: Nephroprotective indications such as: Arterial hypertension Microalbuminuria (especially ≥ 300mg/g) Coronary heart disease Heart failure with reduced ejection fraction Survival benefit (the exact mechanisms are poorly understood) Any murmur that decreases with amyl nitrate has an etiology that is treatable with ACE inhibitors. History of myocardial infarction Nondiabetic-associated chronic kidney disease with proteinuria Scleroderma-associated hypertensive crisis (even if creatinine is elevated!)
ARBs	Valsartan, candesartan, losartan, irbesartan	Same as ACE inhibitors, but second-line treatment (if ACE inhibitors are not tolerated)
Direct renin inhibitors	Aliskiren	Arterial hypertension if both ACE inhibitors and ARBs are not tolerated

References:^{[1][2][3][4][5][6][7][7][8][9]}

	Mechanism of action and effect
ACE inhibitors	Inhibition of ACE → ↓ conversion of angiotensin I to angiotensin II ↓ Angiotensin II ↓ Vasoconstriction → ↓ blood pressure ↓ Secretion of aldosterone → ↓ reabsorption of Na+ and water → ↓ blood pressure Dilation of efferent arteriole → ↑ renal plasma flow → ↓ filtration fraction ↑ Renin secretion (compensatory) → ↑ Angiotensin I ↓ Breakdown of bradykinin → ↑ production of arachidonic acid metabolites → ↑ vasodilation → ↓ blood pressure Other effects: ↓ Proteinuria and ↓ progression of proteinuric kidney disease ↓ Preload and afterload → ↓ cardiac remodeling after acute myocardial infarction or chronic hypertensive disease
ARBs (sartans)	Inhibition of angiotensin II receptor type 1 (AT1 receptors) → ↓ Vasoconstriction → ↓ blood pressure ↓ Secretion of aldosterone → ↓ reabsorption of Na+ and water → ↓ blood pressure ↑ 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
Direct renin inhibitors	Direct inhibition of renin → ↓ conversion of angiotensinogen into angiotensin I → ↓ angiotensin I and angiotensin II → vasoconstriction caused by ↓ angiotensin II ↓ Blood pressure ↓ Secretion of aldosterone → ↓ reabsorption of Na+ and water → further ↓ blood pressure

References:^[2][9][10]

ACE inhibitors

• Dry cough due to increase in bradykinin concentration →
  • Treat by discontinuing ACE inhibitor; consider switching to ARB
• Angioedema
• Hyperkalemia
• Pemphigus vulgaris (unknown mechanism)

ARBs

1. Angioedema
2. Hyperkalemia

Direct renin inhibitors

1. Rash
2. Diarrhea

Acute kidney injury is a potential side effect of all types of RAAS inhibitors, especially in patients with pre-existing kidney disease or in combination with NSAIDs!
References:^[8][11][12]

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
  • Breastfeeding
• Relative contraindications
  • Aortic stenosis
  • Renal dysfunction; consider altering dose if GFR < 60 mL/min
  • Bilateral renal artery stenosis or a solitary kidney
  • Drug interactions (see “Interactions” below)

Contraindications for direct renin inhibitors

• Hypersensitivity
• Drug interactions (see “Interactions” below)

Normally, angiotensin II constricts efferent vessels and thereby increases the GFR. ACE inhibitors antagonize the conversion of angiotensin I to angiotensin II, thereby reducing the GFR!
References:^{[13][14][2][8][15][16]}

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

Do not combine direct renin inhibitors with ACE inhibitors or ARBs, especially in patients with diabetes or pre-existing kidney disease!
References:^{[17][18][19][20][21]}

• Starting with low doses (preferably in 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.

References:^[2][16]