Pharmacology of Angiotensin Receptor Blockers (ARBs)

Introduction/Overview

The renin-angiotensin-aldosterone system (RAAS) represents a critical hormonal cascade in the regulation of blood pressure, fluid balance, and cardiovascular homeostasis. Pharmacological antagonism of this system constitutes a cornerstone in the management of hypertension, heart failure, and chronic kidney disease. Angiotensin receptor blockers, also known as angiotensin II receptor antagonists or AT₁ receptor blockers, are a class of therapeutic agents that selectively inhibit the actions of angiotensin II at the AT₁ receptor subtype. Since the introduction of losartan in the mid-1990s, ARBs have become widely prescribed due to their efficacy and favorable tolerability profile, offering an alternative to angiotensin-converting enzyme (ACE) inhibitors, particularly for patients who develop the characteristic dry cough associated with the latter class.

The clinical relevance of ARBs extends beyond hypertension to encompass a broad spectrum of cardiovascular and renal pathologies. Their importance is underscored by their inclusion in major international treatment guidelines for conditions such as heart failure with reduced ejection fraction, diabetic nephropathy, and post-myocardial infarction care. The pharmacological profile of ARBs, characterized by selective receptor blockade, provides a more complete inhibition of angiotensin II effects compared to ACE inhibitors, as they block angiotensin II generated via both ACE and alternative enzymatic pathways such as chymase.

Learning Objectives

• Describe the molecular mechanism of action of ARBs, including their selective antagonism of the AT₁ receptor and the physiological consequences of this blockade.
• Compare and contrast the pharmacokinetic properties of commonly prescribed ARBs, including absorption, metabolism, elimination pathways, and resultant dosing considerations.
• Identify the approved clinical indications for ARB therapy and the evidence supporting their use in hypertension, heart failure, chronic kidney disease, and cardiovascular risk reduction.
• Analyze the adverse effect profile of ARBs, distinguishing common side effects from serious adverse reactions such as angioedema, hyperkalemia, and teratogenicity.
• Evaluate special considerations for ARB use in specific patient populations, including those with renal or hepatic impairment, the elderly, and during pregnancy.

Classification

Angiotensin receptor blockers are classified based on their chemical structure, which influences their pharmacokinetic properties and receptor-binding characteristics. All ARBs share a common mechanism of action as selective, competitive antagonists of the angiotensin II type 1 (AT₁) receptor, but they are derived from distinct chemical scaffolds.

Chemical Classification

ARBs can be categorized into two primary chemical groups: biphenyl tetrazole derivatives and non-biphenyl non-tetrazole compounds. This classification is relevant as it correlates with differences in bioavailability, metabolism, and potential for drug interactions.

• Biphenyl Tetrazole Derivatives: This group includes losartan, irbesartan, candesartan cilexetil, and olmesartan medoxomil. These agents are prodrugs (with the exception of irbesartan) that require enzymatic hydrolysis in the gastrointestinal tract or liver to form the active moiety. The tetrazole ring is a key pharmacophore for AT₁ receptor binding affinity.
• Non-biphenyl Non-tetrazole Compounds: This group includes valsartan, telmisartan, and eprosartan. These compounds are active in their administered form and possess different anchoring structures, such as an acylated amino acid in valsartan or a benzimidazole ring in telmisartan, that facilitate receptor binding.

Further subclassification may consider pharmacokinetic parameters such as elimination half-life, which distinguishes short-acting agents like eprosartan (t_1/2 ≈5-9 hours) from long-acting agents like telmisartan (t_1/2 ≈24 hours). The presence or absence of active metabolites also provides a basis for differentiation; for instance, losartan is metabolized to an active metabolite (EXP-3174) that is more potent and has a longer half-life than the parent drug, whereas valsartan and irbesartan have no active metabolites.

Mechanism of Action

The pharmacodynamic effects of angiotensin receptor blockers are mediated through selective and competitive inhibition of the angiotensin II type 1 (AT₁) receptor. This receptor is a member of the G protein-coupled receptor (GPCR) superfamily and is ubiquitously expressed in vascular smooth muscle, adrenal cortex, heart, kidney, and brain.

Receptor Interactions and Molecular Mechanisms

Angiotensin II (Ang II) is the primary effector peptide of the RAAS, exerting its physiological actions predominantly via the AT₁ receptor. Upon binding, the activated AT₁ receptor couples primarily to G_q proteins, initiating several intracellular signaling cascades. These include phospholipase C activation leading to inositol trisphosphate (IP₃) and diacylglycerol (DAG) production, intracellular calcium mobilization, protein kinase C activation, and NADPH oxidase activation with subsequent reactive oxygen species generation. This signaling results in potent vasoconstriction, aldosterone and vasopressin secretion, sodium and water reabsorption, sympathetic nervous system activation, and cellular growth and proliferation.

ARBs act as competitive antagonists at the AT₁ receptor binding site. They possess a higher affinity for the receptor than angiotensin II itself, leading to insurmountable antagonism for most ARBs. This insurmountability means that even in the presence of high concentrations of angiotensin II, the receptor blockade cannot be fully overcome, resulting in a persistent inhibitory effect. The molecular basis for this insurmountable antagonism involves slow dissociation kinetics from the receptor and, for some ARBs like candesartan, may involve binding to an allosteric site that stabilizes the receptor in an inactive conformation.

The selectivity for the AT₁ receptor over the AT₂ receptor is a critical feature. Blockade of AT₁ receptors unopposedly increases circulating levels of angiotensin II due to loss of negative feedback on renin release. This elevated angiotensin II may then preferentially stimulate unblocked AT₂ receptors. AT₂ receptor stimulation is generally considered to mediate opposing effects to the AT₁ receptor, including vasodilation, antiproliferative actions, and apoptosis, which may contribute beneficially to the overall therapeutic effects of ARBs.

Cellular and Systemic Pharmacodynamics

At the cellular level, ARB administration attenuates the downstream consequences of AT₁ receptor activation. This includes reduction in vascular smooth muscle cell contraction and hypertrophy, decreased aldosterone synthesis and secretion from the adrenal zona glomerulosa, and inhibition of angiotensin II-mediated norepinephrine release from sympathetic nerve terminals. In the kidney, blockade reduces angiotensin II-induced efferent arteriolar constriction, leading to a decrease in intraglomerular pressure, which is a key mechanism for renal protection in proteinuric kidney diseases.

Systemically, the primary hemodynamic effect is a reduction in peripheral vascular resistance without a compensatory increase in heart rate or cardiac output, as the baroreceptor reflex response may be blunted by inhibition of angiotensin II’s facilitatory role in sympathetic neurotransmission. The reduction in aldosterone levels promotes natriuresis and kaliuresis, although the clinical effect on potassium balance is complex. Over the long term, ARBs exhibit organ-protective effects by inhibiting the pro-fibrotic and pro-inflammatory pathways activated by the AT₁ receptor, which contributes to the regression of left ventricular hypertrophy and slowing of glomerulosclerosis.

Pharmacokinetics

The pharmacokinetic profiles of individual ARBs vary significantly, influencing their dosing regimens, potential for interactions, and suitability for specific patient populations. Key parameters include bioavailability, volume of distribution, plasma protein binding, metabolism, and routes of elimination.

Absorption and Distribution

Oral bioavailability among ARBs ranges widely, from approximately 13% for valsartan to 60-80% for irbesartan and telmisartan. Food can affect the absorption of some ARBs; for example, the absorption of valsartan is reduced by about 40% when taken with food, whereas the bioavailability of losartan and eprosartan is not significantly altered. Most ARBs are rapidly absorbed, with time to peak plasma concentration (T_max) occurring within 1-3 hours for the parent drug, although for prodrugs like candesartan cilexetil and olmesartan medoxomil, T_max for the active metabolite is slightly delayed.

Distribution characteristics are generally favorable for cardiovascular action. ARBs are highly plasma protein bound, primarily to albumin and α₁-acid glycoprotein, with binding exceeding 90% for most agents. Their volumes of distribution are moderate, typically ranging from 10 to 35 L, indicating distribution beyond the plasma compartment. They achieve effective concentrations in target tissues, including vascular walls, heart, and kidney. Telmisartan has a particularly large volume of distribution (≈500 L), reflecting extensive tissue penetration and high lipid solubility.

Metabolism and Excretion

The metabolic fate and elimination pathways of ARBs are diverse and clinically significant.

• Losartan: Undergoes extensive first-pass hepatic metabolism primarily by cytochrome P450 (CYP) enzymes, notably CYP2C9 and CYP3A4, to form its active carboxylic acid metabolite, EXP-3174. This metabolite is 10-40 times more potent than losartan. Approximately 14% of an oral dose is converted to the active metabolite. Both losartan and EXP-3174 are eliminated via biliary and renal routes.
• Valsartan: Is not significantly metabolized. About 20% of an absorbed dose is converted to inactive metabolites. The majority of the drug (≈83%) is excreted unchanged in feces via biliary elimination, with a minor renal component (≈13%).
• Irbesartan: Is metabolized by glucuronidation and oxidation via CYP2C9. It is excreted equally in feces and urine, with less than 2% excreted as unchanged drug.
• Candesartan Cilexetil: Is an ester prodrug hydrolyzed to the active candesartan during absorption from the gastrointestinal tract. It is not metabolized by the CYP system. Excretion is primarily renal (33%) and biliary (67%).
• Telmisartan: Undergoes minimal metabolism, primarily by glucuronidation. It is almost exclusively excreted unchanged in feces via biliary secretion (>97%).
• Olmesartan Medoxomil: Is a prodrug hydrolyzed to olmesartan in the gut and portal blood. It is not metabolized by the liver and is excreted equally in urine and feces.
• Eprosartan: Is minimally metabolized, with about 90% excreted unchanged in feces and bile.

The elimination half-life (t_1/2) dictates dosing frequency. Telmisartan has the longest half-life (≈24 hours), supporting once-daily dosing. Losartan has a short half-life (≈2 hours) but its active metabolite has a half-life of 6-9 hours, also permitting once-daily dosing. Valsartan and eprosartan have intermediate half-lives (≈6-9 hours and 5-9 hours, respectively), which may necessitate twice-daily dosing for full 24-hour blood pressure control in some patients, though they are often administered once daily.

Therapeutic Uses/Clinical Applications

Angiotensin receptor blockers are indicated for a range of cardiovascular and renal conditions, supported by extensive outcome data from large-scale randomized controlled trials.

Approved Indications

• Hypertension: This is the most common indication. ARBs are recommended as first-line agents for uncomplicated hypertension, particularly in patients with specific compelling indications such as left ventricular hypertrophy, diabetic nephropathy, or intolerance to ACE inhibitors. They effectively lower systolic and diastolic blood pressure as monotherapy or in combination with other agents like thiazide diuretics or calcium channel blockers.
• Heart Failure with Reduced Ejection Fraction (HFrEF): ARBs (specifically candesartan, valsartan, and losartan) are indicated to reduce morbidity and mortality in patients with HFrEF who are intolerant to ACE inhibitors. They improve symptoms, reduce hospitalizations for heart failure, and decrease cardiovascular mortality. In some guidelines, they are considered an alternative to ACE inhibitors, though the latter are typically preferred first-line.
• Post-Myocardial Infarction: Valsartan is approved for the reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or dysfunction following acute myocardial infarction. It is considered an alternative in patients intolerant to ACE inhibitors in this setting.
• Diabetic Nephropathy / Chronic Kidney Disease (CKD): ARBs (irbesartan and losartan) are indicated for the treatment of diabetic nephropathy with proteinuria (urinary albumin excretion >300 mg/day) in patients with type 2 diabetes and hypertension. They reduce the rate of progression of renal disease, as evidenced by a reduction in proteinuria and a slower decline in glomerular filtration rate (GFR).
• Stroke Prevention: Based on trial evidence, ARBs may be considered for primary and secondary stroke prevention in hypertensive patients, with some data suggesting a benefit beyond blood pressure lowering, possibly related to effects on vascular remodeling and AT₂ receptor stimulation.

Off-Label Uses

Several off-label applications are supported by clinical evidence, though they may not be formally approved by regulatory agencies in all regions.

• Heart Failure with Preserved Ejection Fraction (HFpEF): While large trials have not consistently demonstrated mortality benefits, ARBs may be used to manage hypertension and symptoms in patients with HFpEF.
• Marfan Syndrome: Losartan is frequently used off-label to slow the rate of aortic root dilation based on its ability to inhibit TGF-β signaling, which is implicated in the cystic medial necrosis characteristic of the disease.
• Migraine Prophylaxis: Candesartan has demonstrated efficacy in reducing the frequency of migraine attacks in some clinical studies, potentially through effects on cerebral vascular tone and neurogenic inflammation.
• Atrial Fibrillation Prevention: Some evidence suggests that ARBs may reduce the incidence of new-onset atrial fibrillation, particularly in patients with left ventricular hypertrophy or heart failure, via reverse remodeling and antifibrotic effects.

Adverse Effects

ARBs are generally well-tolerated, with an incidence of adverse effects comparable to placebo in many clinical trials. Their side effect profile is often considered more favorable than that of ACE inhibitors, particularly regarding cough and angioedema.

Common Side Effects

The most frequently reported adverse reactions are typically mild, dose-related, and often transient.

• Dizziness and Lightheadedness: These effects are often related to the magnitude of blood pressure reduction, particularly upon initiation of therapy or with dose escalation. They are more common in volume-depleted patients.
• Hyperkalemia: Inhibition of aldosterone secretion can impair renal potassium excretion. The risk is increased in patients with renal impairment, diabetes, heart failure, or those concurrently using potassium-sparing diuretics, potassium supplements, or other drugs that raise serum potassium (e.g., NSAIDs, heparin).
• Hypotension: Symptomatic hypotension may occur, especially in patients who are volume- or salt-depleted, such as those on high-dose diuretic therapy.
• Fatigue and Asthenia: These nonspecific symptoms are reported in a small percentage of patients.
• Gastrointestinal Disturbances: Diarrhea, dyspepsia, and nausea have been reported with some ARBs, though no clear class effect exists.

Serious and Rare Adverse Reactions

• Renal Impairment and Acute Kidney Injury (AKI): By reducing efferent arteriolar tone, ARBs can decrease glomerular filtration pressure. In patients whose renal perfusion is critically dependent on angiotensin II (e.g., bilateral renal artery stenosis, severe congestive heart failure, volume depletion), this can precipitate a significant decline in GFR or acute kidney injury. Renal function and serum creatinine should be monitored after initiation or dose increase.
• Angioedema: Although the incidence is significantly lower than with ACE inhibitors (estimated at 0.1-0.3%), angioedema involving the face, lips, tongue, glottis, and/or larynx can occur with ARBs. The mechanism is not fully understood but is thought to be bradykinin-independent. Cross-reactivity between ACE inhibitors and ARBs is possible but not absolute; caution is advised when switching a patient who experienced angioedema on an ACE inhibitor to an ARB.
• Hepatotoxicity: Isolated cases of hepatocellular injury and hepatitis have been reported, particularly with losartan, but this is considered very rare.
• Hematological Effects: Rare cases of neutropenia, agranulocytosis, and thrombocytopenia have been documented.
• Dermatological Reactions: Rash, urticaria, and photosensitivity reactions occur infrequently.

Black Box Warnings

All ARBs carry a black box warning regarding use in pregnancy. Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, ARBs should be discontinued as soon as possible. Exposure during the second and third trimesters is associated with fetal toxicity, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios, presumably from decreased fetal renal function, may also occur and has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Drug Interactions

The potential for clinically significant drug interactions with ARBs is moderate and varies among individual agents based on their metabolic pathways.

Major Drug-Drug Interactions

• Other Antihypertensives: Additive hypotensive effects can occur with concomitant use of other vasodilators, diuretics, beta-blockers, or calcium channel blockers. This interaction is often used therapeutically but requires careful monitoring for excessive blood pressure reduction.
• Potassium-Affecting Agents: Concurrent use with potassium-sparing diuretics (e.g., spironolactone, amiloride, triamterene), potassium supplements, salt substitutes containing potassium, or other drugs that can increase serum potassium (e.g., NSAIDs, heparin, cyclosporine, tacrolimus) significantly increases the risk of hyperkalemia.
• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs, including selective COX-2 inhibitors, may attenuate the antihypertensive effect of ARBs by inhibiting prostaglandin-mediated vasodilation. Furthermore, NSAIDs can impair renal function and reduce potassium excretion, thereby increasing the risk of both acute kidney injury and hyperkalemia when combined with an ARB.
• Lithium: ARBs can reduce renal clearance of lithium, potentially leading to lithium toxicity. Serum lithium concentrations should be monitored closely if co-administration is necessary.
• Drugs Affecting CYP Enzymes: For ARBs metabolized by CYP isoenzymes, interactions are possible. Fluconazole, a potent CYP2C9 inhibitor, can increase plasma concentrations of losartan and its active metabolite. Rifampin, a CYP inducer, may decrease plasma concentrations of losartan. However, for ARBs with minimal CYP metabolism (e.g., valsartan, telmisartan, candesartan), such interactions are unlikely to be clinically significant.
• Aliskiren: Concurrent use of an ARB with aliskiren, a direct renin inhibitor, is generally not recommended due to an increased risk of hyperkalemia, hypotension, and renal impairment, particularly in patients with diabetes or moderate to severe renal impairment.

Contraindications

• Pregnancy: Absolute contraindication in the second and third trimesters; use should be avoided in women planning pregnancy.
• History of Hypersensitivity: Contraindicated in patients with a known hypersensitivity to any component of the formulation.
• Bilateral Renal Artery Stenosis or Stenosis in a Solitary Kidney: Due to the high risk of precipitating acute renal failure.
• Concomitant Use with Aliskiren in Patients with Diabetes: As noted above.
• Severe Hepatic Impairment or Biliary Obstruction: For ARBs that undergo extensive hepatic metabolism or biliary excretion (e.g., losartan, telmisartan), caution is required, and some may be contraindicated in severe impairment.

Special Considerations

Use in Pregnancy and Lactation

As indicated by the black box warning, ARBs are contraindicated during pregnancy due to the risk of fetotoxicity and teratogenicity. Women of childbearing potential should be advised to use effective contraception while taking an ARB. If pregnancy is confirmed, the drug should be discontinued immediately under medical supervision. Regarding lactation, limited data suggest that ARBs are excreted in human milk in small amounts. Because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Valsartan and telmisartan are generally considered compatible with breastfeeding by some sources due to poor oral bioavailability in the infant, but caution is universally advised.

Pediatric and Geriatric Considerations

In pediatric populations, certain ARBs (e.g., losartan, valsartan) are approved for the treatment of hypertension in children aged 6 years and older. Dosing is based on body weight. Pharmacokinetic studies suggest that children may have a higher clearance per body weight than adults, potentially requiring weight-based dosing adjustments. Close monitoring of blood pressure and renal function is essential.

In geriatric patients (≥65 years), no initial dosage adjustment is typically required based on age alone. However, the elderly often have a higher prevalence of reduced renal function, decreased hepatic mass, and concomitant medications, which may increase the risk of adverse effects such as hyperkalemia, hypotension, and renal impairment. A lower starting dose may be prudent, especially in frail elderly patients or those with volume depletion. Age-related decreases in renal function should guide dosing for agents with significant renal excretion (e.g., candesartan, olmesartan).

Renal and Hepatic Impairment

Renal Impairment: Pharmacokinetic alterations in renal failure are variable. For ARBs with significant renal elimination (e.g., candesartan, olmesartan, losartan’s active metabolite), plasma concentrations may be increased in patients with severe renal impairment (GFR <30 mL/min) or end-stage renal disease. More importantly, the pharmacodynamic risk of hyperkalemia and acute kidney injury is markedly increased. It is recommended to initiate therapy at a lower dose, avoid use in volume-depleted patients, and monitor serum potassium and creatinine closely. ARBs are not removed efficiently by hemodialysis due to high protein binding.

Hepatic Impairment: For prodrugs requiring hepatic activation (losartan, candesartan cilexetil, olmesartan medoxomil) or drugs undergoing significant hepatic metabolism (irbesartan), plasma concentrations of the active drug may be altered in patients with hepatic impairment or cirrhosis. In patients with mild to moderate hepatic impairment, dosage adjustment is generally not required for most ARBs. However, for losartan, a lower starting dose is recommended due to increased bioavailability and reduced metabolism. In severe hepatic impairment or biliary obstruction, the use of ARBs that rely heavily on biliary excretion (e.g., telmisartan, valsartan) may be problematic, and therapy should be initiated with caution.

Summary/Key Points

• Angiotensin receptor blockers are selective, competitive antagonists of the angiotensin II type 1 (AT₁) receptor, leading to vasodilation, reduced aldosterone secretion, and inhibition of the detrimental proliferative and fibrotic effects of angiotensin II.
• They are classified chemically as biphenyl tetrazoles or non-biphenyl non-tetrazoles, which influences their pharmacokinetics. Key pharmacokinetic differences include variable bioavailability, presence of active metabolites (losartan), and primary routes of elimination (renal, biliary, or mixed).
• ARBs are first-line agents for hypertension and have proven indications in heart failure (as an alternative to ACE inhibitors), diabetic nephropathy, and post-myocardial infarction left ventricular dysfunction. Off-label uses include Marfan syndrome and migraine prophylaxis.
• The adverse effect profile is favorable, with a lower incidence of cough and angioedema compared to ACE inhibitors. However, risks include hyperkalemia, acute kidney injury (especially in renoprivative states), and fetotoxicity. A black box warning exists for use in pregnancy.
• Significant drug interactions occur with potassium-affecting drugs, NSAIDs, lithium, and other antihypertensives. Contraindications include pregnancy, bilateral renal artery stenosis, and hypersensitivity.
• Special considerations are necessary for patients with renal or hepatic impairment, the elderly, and women of childbearing potential. Dosing often requires adjustment in these populations based on the specific pharmacokinetic profile of the chosen ARB.

Clinical Pearls

• ARBs do not inhibit kininase II (ACE), therefore they are not associated with the accumulation of bradykinin that causes the dry cough and most angioedema seen with ACE inhibitors. They are the preferred alternative in ACE inhibitor-intolerant patients.
• The maximal antihypertensive effect of an ARB may take 2-4 weeks to manifest. Dose titration should not occur more frequently than every 2 weeks.
• When monitoring therapy, a rise in serum creatinine of up to 30% from baseline may be acceptable and is often associated with a greater long-term renoprotective effect in proteinuric kidney disease, provided it stabilizes and hyperkalemia does not occur.
• In heart failure, ARBs should be initiated at low doses with careful monitoring for hypotension and worsening renal function, especially in patients already on diuretic therapy. Dose up-titration should be guided by tolerability and clinical response.
• The choice of a specific ARB may be influenced by comorbidities: telmisartan’s long half-life and PPAR-γ activity may offer theoretical benefits in metabolic syndrome; agents with minimal renal excretion (e.g., telmisartan, valsartan) may be preferred in advanced CKD.

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