Renin-Angiotensin-Aldosterone System Inhibitors

Renin-angiotensin-aldosterone system inhibitors constitute an important drug class for the treatment of cardiovascular disease. They are 1st-line antihypertensive agents, in addition to being used in the treatment of MI, heart failure, diabetic nephropathy, and stroke. Renin-angiotensin-aldosterone system inhibitors include ACEis, ARBs, direct renin inhibitors (DRIs), angiotensin receptor and neprilysin inhibitors (ARNIs), and aldosterone antagonists, which affect different components of the RAAS pathway. In general, the use of RAAS inhibitors results in decreased vasoconstriction and serum blood volume. Common adverse effects include hyperkalemia, cough, angioedema, and pancreatitis, which are all more common with the use of ACEis than ARBs.

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Overview

Definition

Renin-angiotensin-aldosterone system inhibitors constitute an important class of medications for the treatment of cardiovascular diseases, and are 1st-line agents for the treatment of hypertension.

Review of the RAAS

  • Renin (from the kidneys) converts angiotensinogen (from the liver) to angiotensin I.
  • ACE (from the lungs) converts angiotensin I to angiotensin II.
  • Angiotensin II:
    • Binding to angiotensin-1 receptors stimulates:
      • Vasoconstriction and ↑ sympathetic activity
      • Release of aldosterone (from the adrenal cortex), which stimulates Na+ and water reabsorption as well as K+ and H+ secretion
      • Release of antidiuretic hormone (ADH) from the posterior pituitary, which stimulates water reabsorption
      • Direct stimulation of Na+ and water
      • Thirst
    • Binding to angiotensin-2 receptors stimulates:
      • Vasodilation
      • Antiproliferative and cardiovascular-protective effects
    • Chronically ↑ levels of angiotensin II cause:
      • Vascular smooth muscle proliferation
      • Endothelial dysfunction
      • Platelet aggregation
      • Enhanced inflammatory responses
  • The overall effect of RAAS stimulation is to increase BP via:
    • ↑ Effective circulating blood volume
    • ↑ Peripheral vascular resistance
Overview of the renin-angiotensin-aldosterone system

Overview of the RAAS

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Drugs in the RAAS inhibitor class

Drugs in the RAAS inhibitor class include: 

  • ACEis:
    • Captopril (prototypical ACEi)
    • Enalapril (Vasotec®)
    • Lisinopril (Prinivil®, Zestril®)
    • Benazepril (Lotensin®)
    • Multiple others (names ending in “-pril”)
  • ARBs:
    • Losartan (Cozaar®, prototypical ARB)
    • Telmisartan (Micardis®)
    • Valsartan (Diovan®)
    • Multiple others (names ending in “-tan”)
  • Direct renin inhibitors (DRIs): aliskiren 
  • Aldosterone antagonists: spironolactone
  • Angiotensin receptor-neprilysin inhibitor (ARNi): sacubitril/valsartan (Entresto®)

Overview of antihypertensive agents

Table: Drugs used to treat hypertension
Location of action Class Subclass
Renal Drugs affecting the RAAS
  • ACEis
  • ARBs
  • Direct renin inhibitors
Diuretics
  • Thiazide diuretics
  • Loop diuretics
  • K+-sparing diuretics
Extrarenal Direct vasodilators
  • Calcium channel blockers
  • K+ channel openers
  • Nitrodilators
  • Endothelin antagonists
Agents acting via the sympathetic nervous system
  • Drugs affecting CNS sympathetic outflow (e.g., clonidine)
  • Drugs affecting the ganglia (e.g., hexamethonium)
  • Drugs affecting the nerve terminals (e.g., guanethidine, reserpine)
  • Drugs affecting α and β receptors

Chemistry and Pharmacodynamics

Chemical structure

All drugs within a class have the same basic structure but different functional groups attached, which explains their different pharmacokinetic and safety profiles.

  • ACEis: functional groups include carboxyl, sulfhydryl, and phosphinyl groups, which confer different pharmacokinetic properties:
    • Captopril is the prototypical drug (1st in class) containing a sulfhydryl group, which confers antioxidant properties.
    • The prodrug, enalapril, is hydrolyzed to enalaprilat, which has effects similar to those of enalapril.
    • Lisinopril is a lysine derivative of enalaprilat.
    • Other long-acting prodrugs in the class include benazepril, fosinopril, and quinapril.
  • ARBs: include a tetrazole group (ring with 4 nitrogens and a carbon) along with 1 or 2 imidazole groups

Mechanisms of action

Table: Mechanisms of action and physiologic effects
Drug class Mechanism of Action Physiologic effects
ACEis Inhibit ACE, preventing:
  • Conversion of angiotensin I to angiotensin II
  • Degradation of bradykinin (a potent vasodilator)
Decreased peripheral vascular resistance via:
  • ↓ Angiotensin II levels:
    • ↓ Vasoconstriction
    • ↓ Sympathetic activity
    • ↓ Na+ and water reabsorption in the kidney (direct effect)
    • ↓ Aldosterone secretion
  • ↑ Bradykinin:
    • Vasodilation
    • ↑ Risk of cough and angioedema
  • ↓ Efferent arteriole resistance in the kidney → diminished proteinuria and stabilization of renal function in CKD
ARBs Inhibit angiotensin-1 receptors, preventing them from exerting their effects
  • ↓ Angiotensin II activity:
    • ↓ Vasoconstriction
    • ↓ Sympathetic activity
    • ↓ Na+ and water reabsorption in the kidney
    • ↓ Aldosterone secretion
  • No effect on bradykinin
DRis Directly inhibits renin activity, blocking the conversion of angiotensinogen to angiotensin I ↓ Angiotensin I, angiotensin II, and aldosterone → ↓ peripheral vascular resistance
ARNIs Combination of ARB and a neprilysin inhibitor:
  • Inhibits angiotensin-1 receptors
  • Inhibits neprilysin, preventing the degradation of:
    • Natriuretic peptides (ANP, BNP)
    • Vasodilators (bradykinin)
    • Angiotensin II (which is why the neprilysin inhibitor is combined with an ARB)
  • ↓ Vasoconstriction
  • ↓ Aldosterone secretion
  • ↑ ANP, BNP → diuresis
  • ↑ Bradykinin → vasodilation
ANP: atrial natriuretic peptide
DRi: direct renin inhibitor
BNP: brain natriuretic peptide
ARNi: angiotensin receptor-neprilysin inhibitor
Raas inhibitors and their location of action overview

Overview of RAAS inhibitors and their location of action:
ACE inhibitors block both the degradation of bradykinin and the generation of angiotensin II.
ARBs block the angiotensin II type 1 receptors. Direct renin inhibitors block the generation of angiotensin I.
Spironolactone blocks mineralocorticoid receptors at the principal cells in the distal renal tubules and cortical collecting duct.

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

Table: Pharmacokinetics of RAAS inhibitors
Drug Absorption Distribution Metabolism Excretion
ACEis
  • Prodrugs have ↑ bioavailability compared with active drugs
  • Relatively quick onset of action: 15‒60 min
Most drugs have minimal protein binding and relatively modest volumes of distribution Prodrugs are activated via hydrolysis in the liver; active drugs are unchanged.
  • Primarily in the urine
  • Half-life: varies from 2‒24 hours depending on the drug
ARBs
  • Bioavailability: varies
  • Rapidly absorbed orally
  • Vd varies from 0.1 L/kg (candesartan) to a high of 7 L/kg (telmisartan)
  • Protein binding: 95%‒99%
Hepatic metabolism
  • Feces (60%)
  • Urine (35%, approximately 4% as unchanged drug)
  • Half-life: varies from 2‒24 hours
DRI: aliskiren
  • Bioavailability: 3%
  • Poor oral absorption (worsens with meals with ↑ fat content)
Protein binding: 50% Extent of hepatic metabolism unknown
  • Feces (unchanged via biliary excretion)
  • Urine (25% as unchanged drug)
  • Half-life: 24 hours
Vd: volume of distribution
DRI: direct renin inhibitor

Indications

Angiotensin-converting enzyme inhibitors and ARBs

  • Choosing a medication:
    • Indications for ACEis and ARBs are similar. 
    • An ARB may be chosen over an ACEi in patients with (or at high risk for) ACEi-induced side effects, such as cough or angioedema. 
    • Some of these drugs are formulated as combinations with drugs from other antihypertensive classes (e.g., hydrochlorothiazides) → taking a single pill may improve compliance in patients requiring multiple medications
  • FDA-approved indications for the use of ACEis/ARBs:
    • Hypertension (1st-line agent), especially in patients who also have:
      • Type II diabetes mellitus
      • CKD
      • Coronary artery disease (CAD)
    • Diabetic nephropathy
    • Heart failure with reduced ejection fraction
    • STEMI: Treatment within 24 hours improves survival of hemodynamically stable patients.
  • Off-label uses include:
    • Non-ST-elevation acute coronary syndrome (ACS)
    • Stable CAD
    • Proteinuric CKD
    • Posttransplant erythrocytosis in renal transplant recipients
  • Mortality benefits are seen in patients with:
    • Hypertension
    • Heart failure
    • Acute MI
    • Stroke
    • Diabetes mellitus
  • Principles of therapy:
    • ACEis and ARBs are generally not used together except in rare circumstances, generally by nephrologists.
    • ACEis and ARBs are frequently combined with:
      • Diuretics (most commonly, hydrochlorothiazide)
      • Calcium channel blockers
    • ARBs are better tolerated (and more likely to actually be taken by patients) than ACEis.

Direct renin inhibitors and ARNIs

  • DRIs: aliskiren
    • Indicated for hypertension
    • Typically used as “add on” therapy for patients already taking antihypertensives (note: not recommended as initial treatment)
  • ARNIs: sacubitril/valsartan (newer medications and the only drugs in this class)
    • Indicated in patients with chronic heart failure with reduced left ventricular ejection fraction (HFrEF)
    • Shown to reduce cardiovascular death and hospitalizations in patients with HFrEF

Adverse Effects and Contraindications

Adverse effects

The most common adverse effects of ACEis and ARBs are shown in the table.

Table: Adverse effects of ACEis vs ARBs
Symptom ACEis ARBs (and ARNIs)
Hyperkalemia 1% 0.3%
Cough 10%‒20% 1 per 1,000
Pancreatitis 1 per 5,000
  • 1 per 15,000
  • 1 per 10 in patients with a history of pancreatitis due to an ACEi
Angioedema 1 per 2,000 1 per 20,000
ARNI: angiotensin receptor-neprilysin inhibitor

Additional side effects may include: 

  • Hypotension
  • Dizziness/syncope
  • Headache
  • Increase in BUN/creatinine (rarely, ACEis and ARBs can lead to acute renal failure)
  • Diarrhea (with aliskiren)

Contraindications

  • Absolute contraindications:
    • History of angioedema 
    • Pregnancy 
    • Patients with diabetes should not use both a DRI (aliskiren) and an ACEi/ARB.
  • Relative contraindications:
    • Patients with abnormal renal function 
    • Aortic stenosis (ACEis/ARBs are afterload reducers and can lead to severe hypotension)
    • Dehydration/hypovolemia
    • Patients taking other medications that may lead to hyperkalemia (e.g., K+-sparing diuretics)

Comparison of Medications

Table: Comparison of medications commonly used to treat cardiovascular diseases
Medications Mechanisms Physiologic effects Indications
ACEis Inhibit ACE, which:
  • Prevents conversion of angiotensin I to angiotensin II
  • Prevents degradation of bradykinin (a potent vasodilator)
  • ↓ Vasoconstriction
  • ↓ Sympathetic activity
  • ↓ Na+ and water reabsorption
  • ↓ Efferent arteriole resistance (kidney)
  • ↑ Bradykinin
  • Hypertension
  • CHF
  • MI/ACS
  • Diabetic CKD
ARBs Inhibit angiotensin-1 receptors, preventing them from exerting their effects
  • ↓ Vasoconstriction
  • ↓ Sympathetic activity
  • ↓ Na+ and water reabsorption
  • ↓ Efferent arteriole resistance (kidney)
  • Hypertension
  • CHF
  • MI/ACS
  • CKD
Calcium channel blockers Bind to and inhibit L-type calcium channels in cardiac myocytes and vascular smooth muscle
  • Systemic vasodilation
  • ↓ BP
  • ↓ Cardiac afterload
  • ↓ HR
  • ↓ Cardiac output
  • ↓ Myocardial O2 demand
  • Hypertension
  • Stable angina
  • Vasospasm
Beta blockers Inhibit β catecholamine receptors with varying affinity for the β1 vs β2 receptors
  • Negative inotropic and chronotropic effects
  • ↓ Renin release
  • Bronchoconstriction (β2 receptors)
  • Inhibit lipolysis
  • ↓ Intraocular pressure
  • Acute MI
  • Stable heart failure
  • Atrial fibrillation
  • Hypertension (including pregnancy)
  • Open-angle glaucoma
  • Migraine prevention
Thiazide diuretics ↓ Reabsorption of NaCl in the distal convoluted tubule through inhibition of the Na+/chloride cotransporter
  • ↓ Plasma volume → ↓ BP
  • ↓ Edema
  • Hypertension
  • Edema
Loop diuretics Inhibit the luminal Na+/K+/chloride cotransporter in the thick ascending limb of the loop of Henle
  • ↓ Edema
  • ↓ Plasma volume → ↓ BP
  • Edema/ascites
  • CHF
  • Hypertension
K+-sparing diuretics
  • ↓ Reabsorption of Na+ through the ENaC channels in the CD
  • Inhibition of aldosterone receptors in the CD
  • ↓ Plasma volume → ↓ BP
  • ↓ Edema
  • Does not cause ↑ excretion of K+
  • Antiandrogenic effects (spironolactone)
  • CHF
  • Edema/ascites
  • Hypertension
  • Hyperaldosteronism
  • Hirsutism in women (spironolactone)
CHF: congestive heart failure
ACS: acute coronary syndrome
CD: collecting duct
ENaC: epithelial sodium channel

References

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