Pharmacology of Angiotensin Receptor Blockers (ARBs)

Introduction / Overview

Angiotensin receptor blockers (ARBs) represent a pivotal class of antihypertensive agents that selectively inhibit the angiotensin II type 1 (AT₁) receptor. These medications are widely employed in the management of hypertension, heart failure, diabetic nephropathy, and other cardiovascular conditions. Their therapeutic relevance stems from their capacity to attenuate vasoconstriction, aldosterone secretion, and sympathetic outflow without the bradykinin‑mediated side effects that characterize angiotensin‑converting enzyme (ACE) inhibitors. Understanding the pharmacological nuances of ARBs is essential for clinicians and pharmacists to optimize patient outcomes and mitigate adverse events.

Learning objectives:

• Describe the structural and chemical classification of ARBs and their relationship to the renin‑angiotensin‑aldosterone system (RAAS).
• Explain the pharmacodynamic interactions of ARBs with AT₁ receptors and the downstream cellular consequences.
• Summarize the key pharmacokinetic parameters influencing dosing, including absorption, distribution, metabolism, and excretion.
• Identify approved indications and off‑label uses, along with the evidence base supporting each application.
• Recognize common adverse effects, serious complications, and potential drug‑drug interactions that may compromise therapeutic efficacy.
• Apply special considerations for use in pregnancy, lactation, pediatrics, geriatrics, and patients with renal or hepatic impairment.

Classification

Drug Classes and Categories

ARBs constitute a discrete subclass within the broader category of RAAS modulators. They are distinguished from ACE inhibitors by their direct receptor blockade rather than enzymatic inhibition. The principal agents currently available include losartan, valsartan, irbesartan, candesartan, telmisartan, olmesartan, and eprosartan. Each compound shares a core structure featuring a biphenyl or phenyl‑pyrimidine scaffold that confers high affinity for the AT₁ receptor. Variations in substituent groups affect lipophilicity, bioavailability, and metabolic stability, thereby influencing clinical pharmacokinetics.

Chemical Classification

ARBs may be organized according to their heterocyclic core:

• Phenyl‑pyrimidine derivatives (e.g., losartan, valsartan, irbesartan, eprosartan)
• Phenyl‑piperazine derivatives (e.g., candesartan, telmisartan)
• Phenyl‑imidazole derivatives (e.g., olmesartan)

These structural distinctions are relevant when considering drug–drug interactions, as certain metabolic pathways (notably cytochrome P450 3A4) are preferentially involved in the biotransformation of specific subclasses.

Mechanism of Action

Pharmacodynamics

Angiotensin II exerts its principal physiological effects through the AT₁ receptor, which is a G‑protein–coupled receptor expressed in vascular smooth muscle, cardiac myocytes, and renal tubular cells. Upon ligand binding, phospholipase C is activated, leading to increased intracellular calcium and vasoconstriction. ARBs competitively inhibit angiotensin II binding to AT₁ receptors, thereby preventing receptor activation. Because the AT₂ receptor remains unblocked, vasodilatory pathways mediated by nitric oxide and prostaglandins may be preserved, potentially contributing to the favorable tolerability profile of ARBs.

Receptor Interactions

Binding assays have shown that ARBs possess nanomolar affinity for AT₁ receptors, with dissociation constants (K_d) ranging from 2 to 15 nM. The high affinity ensures effective receptor occupancy even at low plasma concentrations. Receptor blockade is reversible; the dissociation rate varies among ARBs, influencing the duration of action. For instance, telmisartan exhibits a prolonged receptor residence time, correlating with its extended half‑life and once‑daily dosing regimen.

Molecular / Cellular Mechanisms

By antagonizing AT₁ receptors, ARBs reduce vasoconstriction, lower systemic vascular resistance, and attenuate aldosterone release from the adrenal cortex. The suppression of aldosterone diminishes sodium and water retention, thereby decreasing extracellular fluid volume. At the cellular level, ARBs inhibit angiotensin II–induced activation of mitogen‑activated protein kinase (MAPK) pathways, reducing myocardial hypertrophy and fibrosis. Additionally, the blockade of AT₁ receptors may modulate the renin‑release feedback loop, leading to modest increases in plasma renin activity that are generally well tolerated.

Pharmacokinetics

Absorption

Oral bioavailability varies among ARBs, ranging from approximately 30% for losartan to >80% for olmesartan. Food intake can influence absorption: losartan’s bioavailability increases by about 20% when taken with a high‑fat meal, whereas olmesartan’s absorption is relatively unaffected by food. Peak plasma concentrations (C_max) are typically achieved between 1 and 4 hours post‑dose (t_max).

Distribution

ARBs are highly protein‑bound, with binding percentages exceeding 90% for most agents. Tissue distribution is extensive, particularly in the kidneys, heart, and vascular wall. The high degree of protein binding limits renal clearance of the unchanged drug, favoring hepatic metabolism and biliary excretion for the majority of ARBs.

Metabolism

Metabolic pathways differ among agents:

• Losartan is rapidly metabolized to an active sulfoxide metabolite (losartan acid) via cytochrome P450 2C9 and 3A4.
• Valsartan undergoes hydrolysis to a phenylacetic acid metabolite, primarily via non‑enzymatic pathways.
• Candesartan and telmisartan are metabolized by CYP3A4 to inactive metabolites.
• Olmesartan is largely excreted unchanged, with minimal hepatic metabolism.

These metabolic distinctions are clinically relevant when considering drug interactions, especially with potent CYP3A4 inhibitors or inducers.

Excretion

Renal excretion accounts for a significant portion of ARB elimination. Losartan acid, the main active metabolite of losartan, is excreted both renally and via the bile. Valsartan and olmesartan are primarily eliminated unchanged by the kidneys. Hepatic excretion constitutes a minor route for most ARBs, except for olmesartan, which may undergo biliary secretion. The overall clearance (CL) ranges from 10 to 30 L/h, depending on the specific agent.

Half‑Life and Dosing Considerations

The elimination half‑life (t_1/2) of ARBs varies widely: losartan 2–3 hours, valsartan 6–9 hours, irbesartan 11–12 hours, candesartan 9 hours, telmisartan 24–27 hours, olmesartan 13 hours, eprosartan 12–15 hours. The extended t_1/2 of telmisartan supports once‑daily dosing, whereas agents with shorter half‑lives may require twice‑daily regimens for optimal BP control. Dose titration is typically guided by clinical response and tolerability, with maximum recommended doses ranging from 100 mg/day for olmesartan to 400 mg/day for telmisartan.

Therapeutic Uses / Clinical Applications

Approved Indications

ARBs are indicated for the following conditions:

• Essential hypertension (monotherapy or combination therapy)
• Heart failure with reduced ejection fraction, often in combination with ACE inhibitors or β‑blockers
• Post‑myocardial infarction to reduce mortality in select patients
• Diabetic nephropathy to slow progression of albuminuria and preserve renal function
• Chronic kidney disease secondary to hypertension or diabetes, particularly when ACE inhibitors are contraindicated due to cough or angioedema

Off‑Label and Emerging Uses

Evidence suggests potential benefits of ARBs in the following contexts:

• Primary prevention of cardiovascular events in high‑risk patients, although guidelines emphasize ACE inhibitors or ARBs with proven mortality benefit.
• Management of resistant hypertension when combined with calcium channel blockers or diuretics.
• Treatment of pulmonary arterial hypertension, with ongoing studies evaluating efficacy and safety.
• Adjunctive therapy in metabolic syndrome to improve insulin sensitivity, albeit with limited robust data.

Clinicians should consider the strength of evidence and guideline recommendations when employing ARBs for off‑label indications.

Adverse Effects

Common Side Effects

ARBs are generally well tolerated. The most frequently reported adverse events include dizziness, headache, fatigue, and orthostatic hypotension. These symptoms are usually mild and may resolve with dose adjustment or gradual titration. Hyperkalemia is a notable laboratory abnormality, particularly in patients with impaired renal function or concurrent use of potassium‑sparing diuretics.

Serious / Rare Adverse Reactions

Serious complications are uncommon but may encompass:

• Severe hyperkalemia leading to cardiac arrhythmias.
• Kidney injury manifested by rising serum creatinine, especially when initiating therapy in patients with pre‑existing renal impairment.
• Aortic dissection or aneurysm rupture, reported infrequently in case series.
• Hypersensitivity reactions such as rash or angioedema, though rare compared to ACE inhibitors.

Black Box Warnings

ARBs carry a black box warning regarding fetal toxicity when used during the second and third trimesters. Exposure is associated with oligohydramnios, renal dysfunction, and potentially death of the fetus. Consequently, ARBs are contraindicated in pregnancy and should be discontinued immediately upon pregnancy confirmation. No black box warning is issued for the general population in the context of cardiovascular or renal indications.

Drug Interactions

Major Drug–Drug Interactions

Key interactions include:

• Potassium‑sparing diuretics (e.g., spironolactone, amiloride) and potassium supplements, which can potentiate hyperkalemia.
• CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) may increase plasma concentrations of certain ARBs (valsartan, candesartan, telmisartan) by reducing metabolism.
• Potent CYP3A4 inducers (e.g., rifampin, carbamazepine) may decrease ARB exposure, potentially diminishing antihypertensive efficacy.
• Non‑steroidal anti‑inflammatory drugs (NSAIDs) may attenuate the antihypertensive effect of ARBs by inhibiting prostaglandin‑mediated renal vasodilation.
• Renin‑stimulating agents (e.g., aliskiren) combined with ARBs can increase the risk of renal impairment and hyperkalemia.

Contraindications

Contraindications encompass:

• Pregnancy (all trimesters), owing to teratogenic risk.
• Severe renal impairment (eGFR <30 mL/min/1.73 m²), particularly with agents that are predominantly renally cleared.
• Known hypersensitivity to the active ingredient or any excipients.
• Simultaneous use of ACE inhibitors or angiotensin receptor neprilysin inhibitors (ARNIs) in patients with known ACE inhibitor hypersensitivity, due to potential additive effects.

Special Considerations

Use in Pregnancy / Lactation

ARBs are contraindicated during pregnancy, especially after the first trimester, because of documented fetal harm. Women of childbearing potential should be advised to use effective contraception while on ARB therapy. The drug is excreted into breast milk in small amounts; however, due to the risk of neonatal hyperkalemia and hypotension, discontinuation is recommended if lactation is intended.

Pediatric / Geriatric Considerations

In pediatric patients, ARBs are approved for hypertension and chronic kidney disease under specific dosing guidelines. Dose adjustments are required based on weight and age. Geriatric patients often exhibit altered pharmacokinetics, including reduced renal clearance and increased plasma protein binding. Initiation at lower doses with gradual titration is advisable to mitigate orthostatic hypotension and hyperkalemia.

Renal / Hepatic Impairment

In patients with chronic kidney disease, cautious dose escalation is warranted. Losartan and olmesartan are preferred in advanced renal impairment due to their minimal renal excretion of the active metabolite. Hepatic impairment may affect metabolism of CYP3A4‑dependent ARBs; dose reductions or avoidance may be necessary in severe hepatic dysfunction. Monitoring of serum creatinine, eGFR, and potassium concentration is essential during therapy initiation and dose adjustment.

Summary / Key Points

• ARBs selectively antagonize AT₁ receptors, providing antihypertensive and organ‑protective effects without the bradykinin‑mediated cough associated with ACE inhibitors.
• Structural diversity among ARBs influences pharmacokinetics, particularly metabolism by CYP3A4 and renal excretion of the active or inactive metabolites.
• The therapeutic profile of ARBs includes hypertension, heart failure, chronic kidney disease, and diabetic nephropathy, with evidence supporting mortality benefit in certain heart failure populations.
• Common adverse effects are mild; hyperkalemia and renal impairment require vigilance, especially when combined with potassium‑sparing agents.
• Black box warning for fetal toxicity necessitates strict avoidance in pregnancy and careful contraception counseling.
• Drug interactions involving CYP3A4 modulators and potassium‑sparing diuretics can alter efficacy and safety; dose adjustments or alternative agents should be considered.
• Special populations, including pregnant women, pediatric patients, the elderly, and those with renal or hepatic impairment, require individualized dosing and monitoring strategies.

Clinical practice should integrate the pharmacodynamic and pharmacokinetic properties of ARBs to tailor therapy, balance efficacy against potential adverse outcomes, and ensure optimal patient care.

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