Angiotensin Receptor Blockers

Introduction

• ARBs are a class of medications that inhibit the binding of ATII to the AT1 receptor in the RAAS pathway.¹
  • By blocking the AT1 receptor, ARBs promote vasodilation, decrease blood pressure, and reduce aldosterone secretion.¹
• ARBs that are widely used include Losartan, Irbesartan, Telmisartan, Eprosartan, Candesartan Cilexetil, and Valsartan.
• ARBs have many clinical uses, primarily for chronic disease states, such as hypertension, CKD, and heart failure with HFrEF.¹
  • ARBs may be beneficial for patients who cannot tolerate the side effects of angiotensin-converting enzyme inhibitors (ACEi), specifically dry cough and/or angioedema.¹
  • In contrast to ACEi, ARBs maintain stimulation of the angiotensin type 2 (AT2) receptor, which promotes vasodilation, natriuresis, and anti-fibrotic effects.²
• ARBs may increase the conversion of ATII to angiotensin-(1-7), which activates the MAS receptor and contributes to additional vasodilatory and anti-inflammatory benefits.³
• ARBs are generally well tolerated; however, they have several adverse effects.
  • Side effects include hypotension, hyperkalemia, reductions in renal function, and dizziness in susceptible patients.¹
  • Collectively, ARBs provide a more complete physiologic blockade of harmful RAAS activity than ACEi, as they block AT1 signaling from both ACE-dependent and chymase-dependent sources, while simultaneously preserving and enhancing AT2 and Mas-mediated protective pathways.^3,4

Mechanism of Action

• ARBs primarily target the RAAS pathway.
• In response to reduced renal perfusion pressure and sympathetic stimulation, the juxtaglomerular cells of the kidney secrete renin.¹
  • Renin stimulates the conversion of angiotensinogen to angiotensin I (ATI).¹
  • ATI is then converted to ATII by the angiotensin-converting enzyme (ACE).¹
  • ACE is the primary enzyme that converts ATI → ATII in acute states. However, during chronic conditions such as heart failure, CKD, and diabetes, tissue chymase becomes the dominant pathway for ATII production.^1,4
  • Chymase-derived ATII is not blocked by ACEi.⁴
• ATII acts through the ATII type 1 (AT1) and type 2 (AT2) receptors.¹
  • The activation of the AT1 receptor leads to increased blood pressure due to smooth muscle contraction, increased systemic vascular resistance, and increased sympathetic activity.¹
  • Additionally, activation of the AT1 receptor stimulates aldosterone secretion from the adrenal zona glomerulosa. Aldosterone increases sodium and water reabsorption by upregulating the epithelial sodium channel (ENac) and the sodium potassium pump.^2,5
  • Thus, ATII is the global activator that increases vascular tone, renal sodium retention, blood volume, blood pressure, vasopressin, sympathetic activity, thirst, aldosterone, and tissue remodeling across the heart, kidney, and vasculature.¹
• ARBs block the binding of ATII to the AT1 receptor.¹
  • Inhibition leads to:
    • Vasodilation
    • Decreased aldosterone secretion, and thus reduced ENaC-mediated Na⁺ reabsorption
    • Decreased blood pressure
• ARBs increase the availability of ATII for conversion by angiotensin-converting enzyme 2 (ACE2) into angiotensin-(1-7), thereby increasing Mas receptor activation without directly upregulating ACE2 expression.³
  • By blocking AT1 receptors, ARBs allow accumulated ATII to interact with ACE2. ATII is converted to angiotensin-(1-7), which then acts on Mas receptors.³
  • Since ARBs block AT1, ATII signaling shifts towards the AT2 receptor, thus promoting vasodilation, natriuresis, anti-fibrotic, anti-proliferative, and nitric-oxide mediated relaxation.²
  • Activation of the Mas receptors induces vasodilation and exerts anti-proliferative, antioxidant, and anti-inflammatory effects.³
  • These effects provide additional cardiovascular and renal protection beyond AT1 blockade.³
• Additionally, with the AT1 receptor blockage, AT2 stimulation is left unopposed.²
  • AT2 receptor activation leads to:
    • Vasodilation
    • Natriuresis
    • Antifibrotic effects
    • Antiproliferative effects

Pharmacokinetics

• The pharmacokinetic properties vary among drugs in this class.
  • Losartan and candesartan cilexetil are prodrugs that are converted into active forms.²
  • Losartan undergoes metabolism in the liver, where it is converted into EXP3174.²
    • EXP3174 lengthens the antihypertensive effect in patients.
  • Candesartan cilexetil undergoes cleavage in the gastrointestinal tract, leaving only the active drug candesartan.²
• The primary route of elimination for ARBs is by biliary excretion:
  • Losartan – biliary excretion (70-80%)²
  • Valsartan – biliary excretion (70-80%)²
  • Irbesartan – biliary excretion (70-80%)²
  • Telmisartan – biliary excretion (<90%)²
  • Candesartan cilexetil – renal (40%) and biliary excretion (40%)²
  • Eprosartan – renal and biliary excretion. The majority of excretion is performed by the kidneys.²
• Although ARBs vary in bioavailability and metabolic pathways, these variations do not significantly alter their overall clinical effectiveness.²

Systemic Effects

• ARBs have several systemic effects through their action on the RAAS cascade.
• Cardiovascular effects include vasodilation, decreased systemic vascular resistance, and reduced afterload.⁶
  • By inhibiting the AT1 receptor, ARBs lower blood pressure and reduce left-ventricular hypertrophy seen in some patients.²
  • ARBs reduce aldosterone secretion, which leads to decreased sodium reabsorption in the collecting duct and partial correction of aldosterone-mediated cardiac fibrosis.⁵
  • ARBs also decrease sympathetic activation by blocking AT1-mediated norepinephrine release.⁵
  • The utilization of ARBs has also been reported to reduce the risk of stroke and heart failure.^1,2
• ARBs have several renal protective effects.
  • ARBs reduce intraglomerular hypertension by dilating the efferent arteriole of the glomerulus. The dilation of the efferent arteriole decreases glomerular capillary pressure and thereby prevents progressive nephron injury.⁵
  • ARBs also reduce proteinuria in both patients with and without diabetes.¹
• Regardless of whether ATII is formed by ACE or chymase, ARBs fully block AT1 signaling. Therefore, ARBs remain highly effective in chronic diseases characterized by structural remodeling, such as hypertension, diabetic kidney disease, and heart failure.^1,4

Clinical Uses

• Although ACE primarily catalyzes the conversion of ATI to ATII, chymase becomes the dominant alternative pathway in chronic conditions affecting the heart, kidney, and liver.⁴
  • During chronic inflammation, mast cell degranulation releases chymase into the surrounding tissue, enabling the conversion of ATI to ATII independent of ACE. Chymase-mediated ATII production promotes tissue remodeling, inflammation, and fibrosis.⁴
  • Therefore, ARBs provide complete inhibition of ATII signaling at the AT1 receptor, irrespective of whether ATII is generated via ACE-dependent or ACE-independent (e.g., chymase) pathways.^1,4
    • This mechanism allows ARBs to be routinely used for the treatment of chronic diseases, such as hypertension, congestive heart failure, and CKD.^1,4
• Antihypertensive efficacy is enhanced when ARBs are combined with ACEi, diuretics, and calcium channel blockers.²
• ARBs can be used in guideline directed medical therapy (GDMT) for HFrEF.
  • Medications typically used in GDMT for HFrEF include angiotensin-receptor neprilysin inhibitors (ARNIs), ARBs, ACEi, beta-blockers, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptors.⁸
  • When initiating GDMT, ARNIs are preferred; however, if this class of medication is not well-tolerated, a patient can be started on ARBs (Losartan or Valsartan).⁸
  • Early initiation of GDMT has been shown to reduce heart failure hospitalizations and mortality.⁸
  • Additionally, ARBs have been shown to reduce left ventricular hypertrophy more effectively than beta-blockers (Atenolol).⁶
• The administration of ARBs has also been reported to improve liver aminotransferase levels in patients with nonalcoholic fatty liver disease by decreasing glutamic-oxaloacetic transaminase levels. However, additional research is needed to fully understand their management.¹

Dosing

• When ARBs are administered, a low dose is recommended and should be titrated as clinically indicated.⁵
• Lower doses of ARBs are also recommended for patients with severe renal or hepatic disease and for those with volume and salt depletion.¹⁰
• If a patient’s creatinine clearance is ≥ 30 mL/min, no dosage adjustment is required.⁹
  • Renal function and serum potassium should be reassessed 1-2 weeks after initiation or dose escalation.¹

Side Effects

• ARBs are well tolerated; however, some side effects have been reported.
  • Headaches, nausea, fatigue, and upper respiratory infections have been reported in patients treated with Losartan.
  • However, the side effects of ARBs occur at rates similar to those of a placebo.^2,5
  • Dizziness has been reported in approximately 2-4% of patients taking ARBs, which is typically associated with a first-dose hypotensive effect. Therefore, a low dose is initially favored, then titrated as needed.⁵
  • Hypotension, particularly in older individuals¹
  • Acute kidney injury, particularly in older individuals¹
  • Unlike ACEi, ARBs do not increase bradykinin levels, explaining their markedly lower rates of cough and angioedema.¹
• A low discontinuation rate with ARBs is ^reported.2

Contraindications

Absolute Contraindications¹

• Hypersensitivity to the drug
• Pregnancy
  • ARBs should be avoided in patients who are pregnant, breastfeeding, or planning to become pregnant, as they have been shown to cause fetal and neonatal morbidity.²
• Bilateral renal artery stenosis
  • Glomerular filtration depends on ATI1-mediated efferent arteriolar constriction in bilateral renal artery stenosis. ARBs block this mechanism, leading to a sharp decline in GFR and potentially precipitating acute kidney injury (AKI).¹¹
  • Thus, ARBs are contraindicated in patients with bilateral renal artery stenosis, as they can precipitate acute renal failure.¹¹
• Coadministration with aliskren in patients with diabetes.¹

Relative Contraindications¹

• Symptomatic hypotension, especially in patients receiving high-dose diuretics or those who are salt-depleted.¹
  • To avoid this risk, salt depletion should be corrected before starting ARBs.¹
• Hyperkalemia
• Acute kidney injury or advanced CKD. Renal function should be monitored often.¹
  • A patient with volume depletion is at an increased risk for acute kidney injury with ARBs. Volume depletion increases the risk of first-dose hypotension and AKI; therefore, hypovolemia should be corrected before the initiation of an ARB.¹
  • With the blocking of AT1-mediated aldosterone secretion from the adrenal zona glomerulosa, ARBs reduce water and sodium reabsorption in the kidneys.^2,5 Excretion of water and sodium occurs at a greater rate.^2,5
  • Patients with volume depletion should avoid ARBs until their volume is corrected.^2,5
  • ARBs also increase the risk of acute kidney injury in patients with acute illnesses, such as sepsis, diarrhea, and heart failure.¹