Angiotensin II Receptor Blockers (ARB)

Mechanism of Action

Renin is secreted by the juxtaglomerular cells of the kidneys and catalyzes the conversion of angiotensinogen to angiotensin I (ATI) in the liver. ATI is then converted to angiotensin II (ATII) by angiotensin-converting enzyme (ACE) and other non-ACE pathways.[10]

ATII is the principal vasoactive peptide in the RAAS and acts on 2 receptors, angiotensin II type 1 (AT1) and type 2 (AT2) receptors. ATII activation of AT1 receptors increases blood pressure by inducing vascular smooth muscle contraction, elevating systemic vascular resistance, and enhancing sympathetic activity. This pathway also promotes sodium and water retention through increased sodium reabsorption in the proximal convoluted tubule. Sodium reabsorption in this region is directly mediated by ATII and indirectly promoted by increased aldosterone production from the adrenal cortex, which enhances distal sodium reabsorption.

Chronically elevated ATII levels contribute to the growth and proliferation of smooth and cardiac muscle cells, endothelial dysfunction, platelet aggregation, increased inflammatory responses, and apoptosis. Conversely, ATII binding to AT2 receptors leads to vasodilation, primarily through increased nitric oxide and bradykinin production.[11] Additionally, AT2 receptor activation promotes renal sodium excretion and exerts antiproliferative and cardiovascular protective effects.[12]

RAAS system blockade can occur at multiple levels. RAAS blockers include direct renin inhibitors (DRIs), which inhibit renin production; ACEIs, which prevent the conversion of ATI to ATII; ARBs, which block the effects of ATII on AT1 receptors; and aldosterone antagonists, which inhibit aldosterone’s effects.[13][14]

Absorption

ARBs exhibit variable oral bioavailability, influenced by their structural properties and formulation. Losartan has an average absolute bioavailability of approximately 33%, valsartan around 25%, and irbesartan between 60% and 80%. Some ARBs, such as candesartan, olmesartan, and azilsartan, are administered as prodrugs and require enzymatic hydrolysis in the gastrointestinal tract to release the active moiety. Food intake affects absorption to varying degrees. For irbesartan and telmisartan, systemic exposure remains generally unaffected by food. All ARBs may be taken with or without food, although eprosartan is recommended to be taken with food.

Distribution

Plasma protein binding is typically high among ARBs, often exceeding 95%, with telmisartan, candesartan, and olmesartan demonstrating binding levels greater than 99%. This binding predominantly occurs with albumin. ARBs have moderate-to-extensive tissue distribution.

Metabolism

The metabolic pathways of ARBs are heterogeneous. Losartan undergoes hepatic biotransformation via cytochrome P450 (CYP) isoenzymes, primarily CYP2C9 and CYP3A4, resulting in the formation of EXP3174, an active metabolite that contributes substantially to its antihypertensive effect. Azilsartan also undergoes metabolism via CYP2C9, although it produces only inactive metabolites. Other ARBs, such as telmisartan, are not metabolized by CYP enzymes and are instead subject to conjugation reactions, primarily glucuronidation. Following conversion from their prodrug forms, candesartan and olmesartan undergo further metabolism, though minimal, and are eliminated mainly in their unchanged form. These characteristics reduce the potential for CYP–mediated interactions.

Excretion

For ARBs such as irbesartan and telmisartan, hepatic clearance accounts for the majority of total elimination. However, renal elimination also plays a significant role for many ARBs. For example, renal excretion accounts for approximately 60% of the total clearance of carboxylosartan (the active metabolite of losartan), 40% for olmesartan and candesartan, 30% for valsartan, 20% for azilsartan, and 10% for losartan.[15]

The terminal elimination half-life varies within the class. Valsartan exhibits a half-life of approximately 6 hours. Irbesartan's half-life ranges from 11 to 15 hours. Longer half-lives are observed with telmisartan (approximately 24 hours) and eprosartan (approximately 20 hours). These pharmacokinetic properties generally support the use of once-daily dosing.

Among ARBs, losartan has uric acid–lowering properties. The drug functions as a uricosuric agent by inhibiting the urate transporter 1 (URAT1) in the renal proximal tubules, thereby lowering uric acid levels.[16]

Administration

Available Dosage Forms and Strengths

All ARBs approved by the U.S. Food and Drug Administration (FDA) are available in oral formulations. Each ARB has specific approved dosages and tablet strengths, which are included in the dosing guidelines.

Indications for the use of ARBs align with those for ACEIs. However, in patients who cannot tolerate ACEI therapy due to an ACEI-induced cough or angioneurotic edema, ARB therapy is an appropriate and suggested alternative. Currently available ARBs, their FDA-approved indications, and adult dosing for these indications are outlined below.

Azilsartan

This medication is available in 40 mg and 80 mg tablets. The initial dose for hypertension is 20 mg by mouth once daily, with a maximum daily dose of 80 mg.

Candesartan 

Candesartan is available in 4 mg, 8 mg, 16 mg, and 32 mg tablets. For hypertension, the initial dose is 16 mg by mouth once daily, with a maximum daily dose of 32 mg. For heart failure, the initial dose ranges from 4 to 8 mg by mouth once daily, with a maximum daily dose of 32 mg.

Eprosartan

This drug comes in 400 mg and 600 mg tablets. The initial dose for hypertension is 600 mg by mouth once daily, with a maximum daily dose of 900 mg.

Irbesartan

Irbesartan is available in 75 mg, 150 mg, and 300 mg tablets. For hypertension, the initial dose is 150 mg by mouth once daily, with a maximum daily dose of 300 mg. In patients with diabetic nephropathy, the initial dose is 75 mg by mouth once daily, with a maximum daily dose of 300 mg.

Losartan

Losartan is available in 25 mg, 50 mg, and 100 mg tablets. For hypertension, the initial dose is 50 mg by mouth once daily, with a maximum daily dose of 100 mg. For stroke prevention in hypertensive patients with a history of left ventricular hypertrophy (excluding African-American patients), the initial dose is 50 mg by mouth once daily, with a maximum daily dose of 100 mg. For the treatment of proteinuria or diabetic nephropathy, the initial dose is 50 mg by mouth once daily, with a maximum daily dose of 100 mg.

Olmesartan

This medication is available in 5 mg, 20 mg, and 40 mg tablets. For hypertension, the initial dose is 20 mg by mouth once daily, with a maximum daily dose of 40 mg.

Telmisartan

Telmisartan comes in 20 mg, 40 mg, and 80 mg tablets. For hypertension, the initial dose is 40 mg by mouth once daily, with a maximum daily dose of 80 mg. To reduce cardiovascular mortality in adults aged 55 years and older who have risk factors for serious cardiovascular events and cannot tolerate ACEIs, the initial dose is 80 mg by mouth once daily, with a maximum daily dose of 80 mg. This dosage also applies to stroke prophylaxis and myocardial infarction prophylaxis.

Valsartan

This drug is available in 40 mg, 80 mg, 160 mg, and 320 mg tablets. For hypertension, the initial dose ranges from 80 mg to 160 mg by mouth once daily, with a maximum daily dose of 320 mg. For reducing cardiovascular mortality in otherwise stable patients with a history of left ventricular failure or left ventricular dysfunction following acute myocardial infarction, the dosing regimen is similar. For heart failure, the initial dose is 20 mg by mouth twice a day, with a maximum daily dose of 160 mg twice daily. Alternatively, the initial dose for heart failure can be 20 to 40 mg by mouth twice a day, with a maximum dose of 160 mg twice daily.

Drug Combinations

ARBs are available in combination with other medications. Some examples include valsartan and amlodipine, irbesartan and hydrochlorothiazide, losartan potassium and hydrochlorothiazide, valsartan and hydrochlorothiazide, and valsartan and nebivolol. Additionally, the combination of valsartan and sacubitril, a neprilysin inhibitor, is approved for reducing the risk of cardiovascular death and decreasing hospitalization for heart failure in patients with chronic heart failure (New York Heart Association or NYHA Class II through IV) and reduced ejection fraction.[17][18]

A few important considerations when using ARBs include ensuring that volume depletion is corrected in patients who are volume-depleted or taking diuretics before starting these agents, or beginning treatment with a lower dose. For patients who experience diminished blood pressure response toward the end of a 24-hour dosing interval, clinicians should consider switching to a 12-hour dosing schedule.

Specific Patient Populations

Medications that diminish renal perfusion or increase the risk of acute kidney injury (AKI), such as nonsteroidal anti-inflammatory drugs, ACEIs, and ARBs, should be avoided in patients with ascites and liver failure. In individuals with normal hepatic function, ARBs can rarely cause drug-induced liver injury (DILI). Most ARB-associated drug-induced liver injury cases are cholestatic and mild, with no consistent dose-dependent pattern, indicating an idiosyncratic mechanism likely influenced by individual patient factors. Close monitoring during the initial weeks of ARB therapy is recommended to identify early signs of hepatotoxicity.[19]

In patients with CKD, ARBs effectively reduce intraglomerular pressure, proteinuria, and the progression to end-stage renal disease, showing benefits in patients with and without diabetes. Clinical trials and meta-analyses have demonstrated that losartan, irbesartan, telmisartan, valsartan, and candesartan significantly reduce proteinuria and slow renal function deterioration.

However, despite its renoprotective effects, olmesartan has been linked to increased cardiovascular mortality in high-risk populations. This association may be due to excessive blood pressure reduction, which is a concern in these patients.[20]

The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend initiating ACEIs or ARBs for individuals with CKD stages G1 to G4 and severely increased albuminuria, regardless of diabetes status. For patients with CKD G1 to G4 and diabetes, ACEIs or ARBs are also recommended if albuminuria is moderately to severely increased.

Importantly, KDIGO strongly advises against combining ACEIs, ARBs, and DRIs in individuals with CKD, regardless of diabetes status, due to the increased risk of adverse events. In cases of symptomatic hypotension or uncontrolled hyperkalemia, clinicians should reduce the dose or discontinue ARBs, particularly in patients with kidney failure and an estimated glomerular filtration rate of less than 15 ml/min per 1.73 m².[21] Notably, higher doses of ARBs are associated with an increased risk of AKI, particularly in patients with comorbid conditions such as heart failure, diarrhea, or sepsis.[22]

ARBs are contraindicated during pregnancy due to potential fetal toxicity. The FDA classifies these drugs under category D, meaning evidence of potential harm to the fetus exists. Patients who may become pregnant while taking ARBs should be counseled on the importance of birth control. These individuals should also be informed about alternative options for controlling blood pressure in case they become pregnant and need to switch to another antihypertensive therapy. If a patient becomes pregnant or suspects pregnancy while on ARBs, the therapy should be discontinued immediately, unless the treatment is deemed lifesaving for the mother.[23]

Research has shown that maternal use of ARBs can lead to adverse fetal outcomes, including renal failure, lung dysplasia, cranial hypoplasia, limb contractures, and even fetal or neonatal death. These effects are believed to result from fetal hypotension and impaired renal blood flow, which can cause kidney ischemia, anuria, and oligohydramnios. Oligohydramnios, in turn, may contribute to limb contractures, craniofacial deformities, and lung dysplasia. Additionally, ARBs may reduce placental and umbilical cord blood flow, leading to fetal growth restriction and potential issues with skull angiogenesis, which could affect skull ossification.[24]

No published evidence supports the safe use of ARBs during breastfeeding, and the potential effects of exposure to these medications in a nursing infant remain unknown.[25] Newborns may be at theoretical risk of hypotension due to the presence of ARBs in breast milk. As such, the decision to continue or stop breastfeeding should involve a thorough discussion between the primary care provider and the patient.

Insufficient evidence exists regarding the concentration of RAAS inhibitors in breast milk and their subsequent effects on newborns. The decision to reintroduce RAAS inhibitors will depend on several factors, including the severity of maternal hypertension that remains uncontrolled despite alternative antihypertensive treatments, the patient's medical history, pregnancy complications that required the use of RAAS inhibitors, and the health and prematurity of the infant.

The American Academy of Pediatrics outlines that ARBs used in the management of pediatric hypertension include losartan, irbesartan, valsartan, candesartan, and olmesartan. The Academy also recommends ARBs or ACEIs for pediatric patients with CKD, hypertension, and proteinuria.[26][27]

A lower dose of ARBs should be considered in adults aged 65 years or older due to increased sensitivity to medication and the potential for adverse effects. This adjustment helps minimize the risk of hypotension and other related complications in this population.

Adverse Effects

ARBs are generally well tolerated, with a low incidence of side effects. The occurrence of angioedema and cough with ARBs is lower compared to ACEIs, as ARBs do not elevate bradykinin levels, although rare cases of both side effects have been reported in patients using ARBs. ARBs may cause hypotension or renal failure in patients whose arterial blood pressure or renal function is highly dependent on the RAAS. Consequently, these drugs are contraindicated in patients with bilateral renal artery stenosis (RAS) or in those with heart failure who experience hypotension.[28] Olmesartan has been associated with sprue-like enteropathy.[29] Other rare adverse effects include urticaria, anaphylaxis, vasculitis, neutropenia, leukopenia, and liver function test abnormalities.[30]

Drug-Drug Interactions

ARBs enhance the blood pressure-lowering effect of other antihypertensive medications, which may necessitate adjusting the dosage of either the ARB or the concomitantly administered antihypertensive drugs. The combination of ARBs with ACEIs or DRIs increases the risk of hypotension, acute renal failure, or hyperkalemia. Due to these risks, the concurrent use of these agents is no longer recommended and should be avoided.[31]

ARBs can further elevate potassium levels in patients with renal disease or those taking medications that promote hyperkalemia, such as potassium supplements, potassium-sparing diuretics, ACEIs, DRIs, or nonsteroidal anti-inflammatory drugs. Caution is advised when prescribing ARBs to these patients; in some cases, avoiding their use may be safer altogether.

Additionally, ARBs can increase serum lithium levels and the risk of toxicity when taken with lithium. Regular monitoring of serum lithium levels and dose adjustments are necessary when these medications are coadministered.[32]

Contraindications

Absolute contraindications to ARBs include hypersensitivity to the drug or its excipients. Angioedema has been reported in patients using ARBs.[33] Additionally, these medications are contraindicated for coadministration with aliskiren in patients diagnosed with diabetes.

Box Warnings

ARBs, like ACEIs, are contraindicated during pregnancy due to the risk of reducing fetal kidney perfusion, which may lead to renal dysgenesis, fetal oliguric or anuric renal failure, oligohydramnios, skeletal or skull deformities, pulmonary hypoplasia, and fetal death. ARB therapy should be discontinued immediately if pregnancy is detected.[34]

Warning and Precautions

In patients with an activated renin-angiotensin system, such as those receiving high-dose diuretics, initiating ARB therapy can lead to symptomatic hypotension. To mitigate this risk, any volume or salt depletion should be corrected before starting therapy. Additionally, ARBs may cause acute renal failure, especially in individuals with RAS, CKD, severe heart failure, or volume depletion. Therefore, renal function should be monitored regularly, and therapy should be discontinued if a clinically significant decline occurs.

Periodic monitoring of serum potassium is necessary, as dosage adjustments or discontinuation of therapy may be required. Concurrent use of ARBs with other agents that increase serum potassium levels must be avoided.[35] At higher doses, ARBs are also associated with an increased risk of AKI, particularly in patients with comorbid conditions such as heart failure, diarrhea, or sepsis.

Monitoring

ARB therapy increases the risk of hypotension, renal impairment, and hyperkalemia. Therefore, blood pressure, renal function, and serum electrolyte levels must be closely monitored during ARB use.[36] Primary care providers should carefully review the patient's full medication list, as lithium concentrations may rise when used with ARBs.[37] In patients with heart failure, monitoring LVEF is essential. During acute decompensation, N-terminal pro B-type natriuretic peptide (NT-proBNP) levels and a chest x-ray should be obtained to assess the patient's condition.[38][39]

Toxicity

A retrospective analysis of 206 monoexposures to ARBs reported to Poisons Information Centres in Austria, Germany, and Switzerland found that most children (82.7%) and over half of adults (53.6%) remained asymptomatic. The median ingested dose reached 2.3 times the maximum recommended daily dose adjusted for body weight in children and 6.8 times in adults. Only 1 pediatric patient developed hypotension requiring intravenous fluid administration after ingesting 8.75 times the maximum recommended daily dose of candesartan. Medical evaluation is advised only for symptomatic individuals or those who have ingested 5 times or more the recommended maximum dose based on body weight.[40]

A literature review on ARB overdose describes a typical presentation of hypotension and shock resulting from vasodilation, marked by a high cardiac index and low systemic vascular resistance. Coingestion with CCBs is frequently reported. Metabolic abnormalities often include normal anion-gap metabolic acidosis and elevated lactate levels, suggesting tissue hypoxia. The shock pattern is vasoplegic rather than cardiogenic, supported by echocardiographic findings of preserved cardiac function.

Hypotension tends to have a delayed onset and prolonged duration, consistent with the long half-life of olmesartan (10–15 hours), and may persist for more than 16 hours postingestion. In one case, the patient’s condition remained resistant to conventional therapies typically used for CCB toxicity, including intravenous fluids, calcium gluconate, glucagon, and high-dose insulin euglycemia therapy.[41]

Initial treatment in the case report focused on supportive measures, including aggressive fluid resuscitation and airway protection through intubation and mechanical ventilation. The patient remained hypotensive despite these interventions and the use of catecholamines, underscoring the limited benefit of these agents in ARB toxicity due to suppression of the sympathetic nervous system. Diagnostic clues pointing to ARB involvement included the failure of CCB-directed therapies and the persistence of vasodilatory shock.

Vasopressin, introduced as a 2nd-line vasopressor, effectively raised mean arterial pressure through vasopressin 1a receptor-mediated vasoconstriction. ATII may also be beneficial as a vasopressor in shock related to ARB overdose. The patient responded favorably, with vasopressor support discontinued by day 3 and full recovery achieved without sequelae. Extracorporeal membrane oxygenation remains a potential option for patients with cardiorespiratory failure who deteriorate despite maximal supportive therapy.[42]

Enhancing Healthcare Team Outcomes

Effective hypertension management often requires a comprehensive approach involving physicians, advanced practice providers, nurses, pharmacists, and relevant specialists. Comorbid conditions such as diabetes, heart failure, renal impairment, and obesity frequently coexist with hypertension and warrant collaborative care across multiple specialties. ARB therapy remains a key option for patients with hypertension and concomitant diabetes or heart failure. Initiating treatment early following diagnosis improves outcomes, emphasizing the importance of prompt intervention, particularly as cardiovascular disease increasingly affects younger individuals.[43]

Initiating ARB therapy benefits from active involvement of a pharmacist to verify appropriate dosing, identify potential drug interactions or contraindications, counsel patients, and communicate concerns to the prescriber. Nurses contribute by addressing patient questions, providing instruction on proper administration, and maintaining communication with both the prescriber and the pharmacist. This collaborative approach optimizes patient outcomes. Physicians and advanced practice providers are responsible for initiating, monitoring, and adjusting ARB therapy, while critical care specialists manage overdose cases.

In addition to pharmacologic management, physicians should encourage lifestyle modifications such as weight loss, which may reduce systemic inflammation and improve systolic blood pressure.[44] Ongoing communication among clinicians, pharmacists, and nurses is essential to reduce adverse effects and maximize the therapeutic benefit of ARB treatment.