Landiolol: A Comprehensive Monograph on an Ultra-Short-Acting, Highly Cardioselective β1-Adrenergic Antagonist

I. Foundational and Chemical Profile

1.1 Identification and Nomenclature

Landiolol is a small molecule drug classified as a cardioselective beta-adrenergic antagonist.[1] It is identified within major drug databases by its DrugBank Accession Number, DB12212, and its Chemical Abstracts Service (CAS) Registry Number, 133242-30-5.[1] The hydrochloride salt form, which is commonly used in clinical formulations, is identified by CAS Number 144481-98-1.[3]

The compound is known by a variety of chemical names and synonyms across scientific literature and regulatory documents. Its International Union of Pure and Applied Chemistry (IUPAC) name ismethyl 3-(4-{(2S)-2-hydroxy-3-[{2-[(morpholin-4-ylcarbonyl)amino]ethyl}amino]propoxy}phenyl)propanoate.[1]

Common synonyms for Landiolol include:

• ONO-1101 [2]
• LDLL600 [3]
• (-)-2,2-dimethyl-1,3-dioxolan-4S-ylmethyl 3-[3-[2-(morpholinocarbonylamino)ethylamino]-2S-hydroxypropoxy]phenyl]propionate [1]
• methyl 3-(4-{(2S)-2-hydroxy-3-[{2-[(morpholin-4-ylcarbonyl)amino]ethyl}amino]propoxy}phenyl)propanoate [1]

This precise chemical identification is fundamental to ensuring the accurate attribution of all subsequent pharmacological, pharmacokinetic, and clinical data to the correct molecular entity, preventing ambiguity in research and clinical practice.

1.2 Molecular Structure and Physicochemical Properties

Landiolol's distinct therapeutic profile is a direct consequence of its specific molecular structure and resulting physicochemical properties. Its chemical formula is C25​H39​N3​O8​, corresponding to an average molecular weight of approximately 509.6 g/mol and a precise monoisotopic mass of 509.273715228 Da.[1]

Structurally, Landiolol is a member of the morpholine class of compounds and is synthesized as a pure S-enantiomer.[2] The molecule possesses two asymmetric carbon atoms, and the therapeutically active form is the specific SS-isomer.[10] This stereochemical purity is a critical design feature. In pharmacology, different enantiomers of a chiral drug can exhibit vastly different affinities for their target receptors and may even produce opposing or off-target effects. The deliberate synthesis of the pure S-enantiomer of Landiolol was a strategic choice to maximize its affinity and selective interaction with the β1-adrenergic receptor while minimizing interactions with other receptors, particularly the β2-receptor. This optimization of stereochemistry is a key contributor to the drug's high cardioselectivity and its favorable safety profile, most notably the reduced incidence of hypotension compared to racemic or less selective beta-blockers.[4]

A pivotal feature of Landiolol's structure is the presence of an ester moiety.[8] This ester bond is the molecular Achilles' heel that makes the compound highly susceptible to rapid enzymatic cleavage in the bloodstream. This is a classic example of "soft drug" design, where a molecule is intentionally engineered with a metabolically labile point to ensure a predictable, rapid, and controlled termination of its biological activity. The hydrolysis of this ester bond by plasma esterases is the direct cause of Landiolol's ultra-short duration of action, a defining characteristic of its pharmacokinetic profile.[8]

The physicochemical properties of Landiolol are summarized in Table 1. It is a white to off-white powder that is very soluble in water.[10] Its large topological polar surface area (TPSA) of 127.82 Ų contributes to its low membrane permeability, which explains its lack of appreciable pharmacochaperoning activity.[5] According to an analysis based on Lipinski's rules of five, which predict oral bioavailability, Landiolol violates three of the rules.[5] This is expected and clinically irrelevant, as the drug is designed exclusively for intravenous administration where oral absorption is not a factor.

Table 1: Chemical and Physical Properties of Landiolol

Property	Value	Source(s)
Identifiers
DrugBank ID	DB12212	1
CAS Number (free base)	133242-30-5	2
CAS Number (HCl salt)	144481-98-1	3
ATC Code	C07AB14	2
Molecular Properties
Chemical Formula	C25​H39​N3​O8​	1
Average Molecular Weight	509.6 g/mol	1
Monoisotopic Mass	509.273715228 Da	1
Stereochemistry	Pure S-enantiomer (SS-isomer)	8
Physicochemical Properties
Boiling Point (Predicted)	727.5±60.0 °C	2
Density (Predicted)	1.201±0.06 g/cm³	2
pKa (Predicted, acidic)	13.73	2
Water Solubility (HCl salt)	0.163 mg/mL	12
Topological Polar Surface Area	127.82 Ų	5
Rotatable Bonds	16	5
Pharmacological Properties
β1/β2 Selectivity Ratio	255:1	2

II. Pharmacological Profile: Mechanism and Disposition

The clinical utility of Landiolol is defined by the interplay of its pharmacodynamic actions at the receptor level and its unique pharmacokinetic disposition within the body. This combination results in a highly titratable and predictable therapeutic effect, optimized for the acute care setting.

2.1 Pharmacodynamics

Mechanism of Action

Landiolol functions as a highly selective, competitive antagonist of the β1-adrenergic receptor.[1] These receptors are predominantly located in the cardiac muscle (myocardium) and the heart's conduction system.[1] In physiological states, particularly during stress, surgery, or in conditions like sepsis, the sympathetic nervous system releases catecholamines (epinephrine and norepinephrine). These catecholamines bind to β1-receptors, activating intracellular signaling pathways that lead to an increase in heart rate (positive chronotropy), force of contraction (positive inotropy), and speed of electrical conduction.[1]

By competitively blocking these receptors, Landiolol effectively antagonizes the effects of circulating catecholamines, thereby reducing the sympathetic drive on the heart. This blockade manifests as several key electrophysiological and mechanical effects:

• Reduction of Heart Rate: It slows the rate of depolarization in the sinoatrial (SA) node, the heart's primary pacemaker.[1]
• Decreased Ectopic Firing: It suppresses the spontaneous firing of abnormal pacemaker sites within the atria and ventricles.[1]
• Slowing of AV Nodal Conduction: It prolongs the conduction time through the atrioventricular (AV) node, which is critical for controlling the ventricular response rate in atrial tachyarrhythmias like atrial fibrillation and atrial flutter.[1]
• Increased AV Nodal Refractory Period: It makes the AV node less responsive to rapid atrial impulses, further filtering the signals that reach the ventricles.[1]

Unlike some other beta-blockers, Landiolol does not possess any intrinsic sympathomimetic activity (it does not partially activate the receptor) or membrane-stabilizing activity (local anesthetic effect) at clinically relevant doses.[1]

Receptor Selectivity and Potency

The defining pharmacodynamic characteristic of Landiolol is its exceptional cardioselectivity. It has a significantly greater affinity for β1-receptors than for β2-receptors, which are primarily located in the bronchial and vascular smooth muscle.[13] The reported β1/β2 selectivity ratio for Landiolol is approximately 255:1.[2] This makes it one of the most cardioselective beta-blockers available. For comparison, the selectivity ratio for esmolol is approximately 30-33:1, and for metoprolol, it is approximately 3:1.[2]

In addition to its selectivity, Landiolol is highly potent. Animal studies have shown it to be 6 to 12 times more potent than esmolol in its ability to block catecholamine-induced increases in heart rate.[2] This higher potency translates directly to clinical practice, where the therapeutic infusion rates for Landiolol (e.g., 1-40 mcg/kg/min) are substantially lower than those required for esmolol (e.g., 25-300 mcg/kg/min).[9]

Cardiovascular Effects

Landiolol's high selectivity and potency result in a unique cardiovascular effect profile that is particularly advantageous in critically ill patients. It produces a potent negative chronotropic effect, effectively reducing heart rate, while exerting a demonstrably weaker negative inotropic effect compared to other beta-blockers.[1] Studies in isolated heart preparations have confirmed that while both Landiolol and esmolol reduce heart rate, Landiolol has a less pronounced depressive effect on myocardial contractility.[9]

This dissociation between heart rate control and contractility, combined with its high β1-selectivity that minimizes β2-mediated peripheral vasodilation, leads to superior hemodynamic stability. A consistent finding across preclinical and clinical studies is that Landiolol effectively reduces heart rate with minimal impact on mean arterial blood pressure.[1] This allows for the safe management of tachyarrhythmias even in patients with borderline hypotension or compromised cardiac function, where the blood pressure-lowering effects of less selective agents would be prohibitive. Furthermore, preclinical and clinical investigations have suggested that Landiolol may confer additional anti-ischemic and cardioprotective benefits, likely by reducing myocardial oxygen demand through heart rate reduction without compromising coronary perfusion pressure.[1]

2.2 Pharmacokinetics

The pharmacokinetic profile of Landiolol is characterized by its rapid onset, predictable dose-response, and ultra-short duration of action, all of which are essential for its use as a titratable agent in acute care.

Administration and Distribution

Landiolol is administered exclusively as a continuous intravenous infusion in a closely monitored environment.[18] Its onset of action is extremely rapid, with a reduction in heart rate observed almost immediately upon initiation of the infusion.[4] Pharmacokinetic studies show that steady-state plasma concentrations are achieved within approximately 15 minutes of starting a continuous infusion.[11] The drug exhibits dose-proportional pharmacokinetics over the clinically recommended infusion range, meaning that a doubling of the infusion rate results in a predictable doubling of the plasma concentration.[11]

Following administration, Landiolol has a small volume of distribution, estimated at 0.3 to 0.4 L/kg.[11] This indicates that the drug is largely confined to the central (vascular) compartment. This is further supported by its minimal binding to plasma proteins, which is less than 10%.[1] This low protein binding and small volume of distribution ensure that a high fraction of the drug is readily available to act on cardiac receptors and, just as importantly, is available for rapid elimination from the body.

Metabolism and Biotransformation

Landiolol undergoes rapid and extensive metabolism, which is the primary determinant of its short half-life. The metabolic pathway is independent of the cytochrome P450 (CYP450) enzyme system, a feature that significantly reduces its potential for many common drug-drug interactions.[8] This is a notable advantage in the critical care setting, where patients are often receiving multiple medications that are substrates, inhibitors, or inducers of CYP enzymes. The predictable clearance of Landiolol, unaffected by the status of a patient's CYP enzyme activity, enhances its safety and reliability in complex polypharmacy scenarios.

The primary metabolic pathway is the hydrolysis of the drug's ester moiety.[8] This reaction is catalyzed by non-specific esterases, primarily pseudocholinesterases and carboxylesterases, which are abundant in the plasma, liver, and other tissues.[1] This hydrolysis cleaves the Landiolol molecule, yielding several components: a ketal which is further broken down to glycerol and acetone, and two main metabolites, designated M1 (a carboxylic acid) and M2 (a substituted benzoic acid).[1]

Critically, these metabolites are essentially pharmacologically inert. The beta-blocking activity of M1 and M2 is 1/200th or less than that of the parent Landiolol compound.[1] This ensures that as the parent drug is cleared, its therapeutic effect ceases promptly, without any lingering activity from its breakdown products. This clean metabolic profile is essential for the drug's rapid offset of action.

Elimination

The primary route of elimination for Landiolol and its inactive metabolites is renal excretion.[1] Following a 60-minute intravenous infusion, 89% to 99% of the administered dose is recovered in the urine within 24 hours, primarily as metabolites M1 and M2, with only about 8% excreted as the unchanged parent drug.[11]

The total body clearance of Landiolol is very high, reported at 57 mL/kg/min.[1] This rapid clearance, driven by its swift metabolism, results in an exceptionally short elimination half-life (

t1/2​). Depending on the study and dosing regimen, the half-life is consistently reported to be in the range of 2.3 to 4.5 minutes.[2] This ultra-short half-life is the cornerstone of its clinical utility, allowing for precise, minute-to-minute control of its beta-blocking effect. If adverse effects such as excessive bradycardia or hypotension occur, simply discontinuing the infusion leads to a rapid reversal of the drug's action, with heart rate typically returning to baseline levels within 30 minutes.[4]

The entire pharmacokinetic and pharmacodynamic profile of Landiolol appears to be deliberately optimized for use in hemodynamically unstable, critically ill patients. In clinical settings such as sepsis or post-cardiac surgery, patients often present with tachyarrhythmias but are unable to tolerate the negative inotropic or hypotensive effects of conventional beta-blockers.[17] Landiolol's high β1-selectivity minimizes β2-mediated adverse effects like vasodilation and bronchoconstriction, while its weaker negative inotropy helps preserve myocardial function.[1] This combination of properties, coupled with its ultra-short half-life that permits immediate reversal of effects, creates a pharmacological profile that is not merely advantageous but seems specifically engineered for the precise and safe management of heart rate in the most fragile patient populations.

Table 2: Comparative Pharmacological Profile of Landiolol, Esmolol, and Metoprolol

Parameter	Landiolol	Esmolol	Metoprolol (IV)
Pharmacodynamics
β1/β2 Selectivity Ratio	~255:1	~30:1	~3:1
Relative Negative Inotropic Effect	Weak	Moderate	Moderate-Strong
Relative Hypotensive Effect	Minimal	Moderate	Moderate
Intrinsic Sympathomimetic Activity	No	No	No
Membrane Stabilizing Activity	No	No	Yes (weak)
Pharmacokinetics
Onset of Action	< 1 minute	1-2 minutes	5-10 minutes
Elimination Half-Life	~3-4 minutes	~9 minutes	~3-4 hours
Primary Metabolism Pathway	Plasma/Liver Esterases	Erythrocyte Esterases	Hepatic CYP2D6
Active Metabolites	No	No	No (significant)
Offset of Effect (post-infusion)	< 30 minutes	30-60 minutes	Several hours
Sources: 2

III. Clinical Efficacy and Therapeutic Applications

The unique pharmacological profile of Landiolol translates into specific clinical applications where rapid, titratable, and hemodynamically stable heart rate control is paramount. Its efficacy has been established through a series of clinical trials leading to regulatory approvals in major global markets.

3.1 Approved Indications and Dosing Regimens

Primary Indications

In the United States, Landiolol (marketed as Rapiblyk) is indicated for the short-term reduction of ventricular rate in adults with supraventricular tachycardia (SVT), which includes atrial fibrillation and atrial flutter.[1] Its use is intended for acute care in monitored settings such as the intensive care unit (ICU), emergency department, or operating room, and it is explicitly not intended for chronic management.[1]

In other regions, the approved indications are broader. In Europe and Japan, Landiolol is also approved for the treatment of non-compensatory sinus tachycardia.[9] Japan, where the drug has the longest history of clinical use, has further expanded its approved indications to include the management of tachyarrhythmias associated with sepsis and for tachyarrhythmias in patients with deteriorated cardiac function.[26]

Dosing and Administration

Landiolol is administered as a continuous intravenous infusion, with the dose carefully titrated based on the patient's ventricular rate and hemodynamic status. The dosing recommendations differ significantly based on the patient's underlying cardiac function, a clinical reflection of the drug's potential, albeit weak, negative inotropic effects.

The stark difference in starting doses for patients with normal versus impaired cardiac function is a direct clinical translation of this risk profile. The recommended starting dose for patients with impaired cardiac function (1 mcg/kg/min) is nearly an order of magnitude lower than for those with normal function (9 mcg/kg/min).[18] This cautious "start low, go slow" approach in patients with compromised contractility is a critical risk mitigation strategy. It allows clinicians to carefully titrate to the desired chronotropic effect while closely monitoring for any signs of hemodynamic decompensation, which could be precipitated by even a small additional negative inotropic insult.[19] This dosing guidance is a practical embodiment of the drug's safety profile. The recommended dosing regimens are detailed in Table 3.

Table 3: Recommended Intravenous Dosing and Administration of Landiolol (Rapiblyk®)

Patient Population	Starting Dose	Titration Interval	Titration Step	Maximum Dose
Normal Cardiac Function	9 mcg/kg/min	10 minutes	9 mcg/kg/min	36 mcg/kg/min
Impaired Cardiac Function	1 mcg/kg/min	15 minutes	1 mcg/kg/min	36 mcg/kg/min
Sources: 18

Transitioning to Oral Therapy: When a patient is stable enough to transition to a long-term oral beta-blocker, a specific protocol is recommended to ensure continuous heart rate control. Ten minutes after the first dose of the oral agent is administered, the Landiolol infusion rate should be reduced by 50%. If satisfactory heart rate control is maintained for at least one hour, the Landiolol infusion can then be discontinued.[18]

3.2 Evidence from Clinical Trials

Supraventricular Tachycardia, Atrial Fibrillation, and Atrial Flutter

The U.S. Food and Drug Administration (FDA) approval of Landiolol was supported by a robust data package from five randomized, double-blind, placebo-controlled clinical trials that included a total of 317 adult patients.[15] These pivotal studies consistently demonstrated the efficacy of Landiolol for acute ventricular rate control. A therapeutic response, defined as a greater than 20% decrease in heart rate, a heart rate below 100 beats per minute, or at least intermittent cessation of the arrhythmia, was achieved in 40% to 90% of patients treated with Landiolol. This response was typically observed within 10 minutes of initiating the infusion. In contrast, only 0% to 11% of patients receiving placebo achieved a similar response.[15]

Perioperative Tachycardia

Landiolol has an extensive history of use in the perioperative setting, as this was its initial indication upon approval in Japan in 2002.[2] Clinical studies and real-world experience have shown its effectiveness in managing both intraoperative and postoperative tachyarrhythmias. It has been shown to stabilize hemodynamics in ICU patients following surgery and can serve as an effective "bridge" therapy, providing acute rate control until a patient is stable enough to be transitioned to a chronic oral beta-blocker.[31]

Use in Sepsis and Septic Shock

The role of Landiolol in managing sepsis-related tachycardia is an area of significant clinical interest and evolving evidence. Pathophysiologically, persistent tachycardia in sepsis is associated with poor outcomes, making heart rate control a logical therapeutic target.[22] Initial studies were promising; for instance, a study of septic patients with SVT demonstrated that Landiolol could safely and effectively reduce heart rate from an average of 145 bpm to 90 bpm without causing hemodynamic deterioration, and in some cases, facilitated conversion to normal sinus rhythm.[17]

However, this presents a clinical paradox. While Landiolol is highly effective at achieving the physiological goal of heart rate reduction, larger and more recent randomized controlled trials (such as J-Land 3S, STRESS-L, and Landi-SEP) have failed to show that this translates into improved hard clinical outcomes.[22] These trials demonstrated that while Landiolol effectively controls heart rate, it does not significantly reduce 28-day mortality or decrease the severity of organ failure when compared to standard care.[32] Furthermore, a meta-analysis of these trials highlighted a statistically significant increase in the risk of hypotension in patients treated with Landiolol, advising caution in this population.[22] This discrepancy suggests that tachycardia in sepsis may function more as a marker of underlying disease severity rather than a primary, modifiable driver of mortality. Targeting this single parameter may not be sufficient to alter the course of the complex systemic inflammatory and metabolic dysfunction that characterizes severe sepsis. The clinical implication is that Landiolol should be used judiciously in septic patients, primarily for the management of specific tachyarrhythmias, rather than with the expectation that it will independently improve survival.

Investigational Uses

The unique properties of Landiolol have prompted research into other potential applications. An ongoing clinical trial is investigating its use for rate control in patients with decompensated heart failure who develop atrial fibrillation, a challenging population where negative inotropic effects are a major concern.[35] Another novel area of research is exploring whether perioperative administration of Landiolol could reduce the risk of cancer recurrence following curative surgery, based on the hypothesis that blunting the perioperative stress response may have anti-tumor effects.[36]

IV. Safety, Tolerability, and Risk Management

The responsible clinical use of Landiolol requires a thorough understanding of its safety profile, including potential adverse effects, contraindications, and significant drug-drug interactions. The safety profile of Landiolol is a direct and logical extension of its pharmacodynamic actions.

4.1 Adverse Events Profile

Common and Serious Adverse Reactions

The most frequently reported adverse event associated with Landiolol is hypotension.[15] In placebo-controlled clinical trials, hypotension occurred in approximately 9.9% of patients receiving Landiolol, compared to just 1% in placebo groups.[15] Bradycardia, an expected consequence of its beta-blocking mechanism, is also a common side effect.[14] Both hypotension and bradycardia are typically dose-dependent and, due to the drug's ultra-short half-life, are rapidly reversible upon reduction of the infusion rate or discontinuation of the drug.[17]

While less common, more serious cardiovascular adverse events can occur. These include severe bradycardia leading to sinus pause, high-degree atrioventricular (AV) block, precipitation or worsening of cardiac failure, and cardiogenic shock.[1] Infusion site reactions, such as pain, erythema, and swelling, have also been reported, and administration into large veins is recommended to minimize this risk.[19]

Overdose Effects

An overdose of Landiolol can lead to an exaggeration of its pharmacological effects, resulting in severe cardiovascular and central nervous system toxicity. Cardiovascular signs of overdose include profound bradycardia, all degrees of AV block, junctional rhythms, decreased cardiac contractility, severe hypotension, cardiac failure, cardiogenic shock, and potentially cardiac arrest or pulseless electrical activity.[1] Central nervous system effects can include respiratory depression, seizures, fatigue, lethargy, and coma. Other potential systemic effects of a significant overdose include bronchospasm (from non-selective β2-blockade at high concentrations), hyperkalemia, and hypoglycemia.[1]

4.2 Contraindications and Precautions

The entire risk management strategy for Landiolol, from absolute contraindications to specific warnings, is logically derived from its selective antagonism of the β1-receptor.

Absolute Contraindications

Landiolol is strictly contraindicated in patients with conditions where its beta-blocking effects would be immediately life-threatening. These include [18]:

• Severe Bradycardia: Pre-existing severe sinus bradycardia (heart rate < 50 beats per minute).
• Significant Conduction Disease: Sick sinus syndrome or second- or third-degree AV block in patients without a functioning pacemaker.
• Severe Heart Failure: Decompensated heart failure or cardiogenic shock, where the negative inotropic effects could precipitate further cardiovascular collapse.
• Severe Hypotension.
• Pulmonary Hypertension: May precipitate cardiorespiratory decompensation.
• Hypersensitivity: Known hypersensitivity or anaphylactic reaction to Landiolol or any of its components.

Warnings and Precautions

Close monitoring and caution are warranted in several patient populations where the risks of beta-blockade are increased:

• Reactive Airway Disease: In patients with asthma or severe chronic obstructive pulmonary disease (COPD), beta-blockers should generally be avoided. Although Landiolol is highly β1-selective, this selectivity is relative, not absolute. At higher doses, β2-receptor blockade can occur, potentially leading to life-threatening bronchospasm. If its use is deemed essential, it must be initiated at the lowest possible dose with extreme caution and readiness to treat bronchospasm.[18]
• Diabetes Mellitus: Beta-blockers can mask the adrenergic warning signs of hypoglycemia, particularly tachycardia. This can delay recognition and treatment of low blood sugar. Therefore, frequent blood glucose monitoring is essential in diabetic patients receiving Landiolol.[18]
• Coronary Artery Disease: As with all beta-blockers, abrupt discontinuation of Landiolol in patients with underlying coronary artery disease should be avoided. The sudden withdrawal of beta-blockade can lead to a rebound increase in sympathetic activity, potentially exacerbating angina, precipitating myocardial ischemia, or causing ventricular arrhythmias.[18]
• Other Conditions: Caution is also advised for use in patients with Prinzmetal's angina (where unopposed alpha-receptor stimulation can worsen coronary vasospasm), untreated pheochromocytoma, severe peripheral circulatory disorders, and significant metabolic acidosis.[18]

4.3 Significant Drug-Drug Interactions

The most clinically important interactions with Landiolol are pharmacodynamic in nature, involving additive effects with other cardioactive medications.

Table 4: Clinically Significant Drug-Drug Interactions with Landiolol

Interacting Agent(s)	Potential Effect	Clinical Management Recommendations	Source(s)
Calcium Channel Blockers (non-dihydropyridine; e.g., verapamil, diltiazem)	Additive negative chronotropic, inotropic, and dromotropic (conduction) effects. Increased risk of severe bradycardia, AV block, and myocardial depression.	Concurrent IV use is generally contraindicated or requires extreme caution with intensive hemodynamic monitoring.	14
Other Beta-Blockers (oral or IV)	Additive beta-blocking effects, leading to excessive bradycardia and hypotension.	Concurrent use should be avoided unless part of a carefully planned transition strategy with dose reduction.	14
Antiarrhythmic Agents (e.g., amiodarone, digoxin)	Increased risk of bradycardia and AV conduction disturbances.	Requires continuous ECG and hemodynamic monitoring.	1
Catecholamine-Depleting Drugs (e.g., reserpine)	May produce an exaggerated beta-blocking response (severe bradycardia, hypotension) due to depleted sympathetic tone.	Close observation for signs of hypotension and marked bradycardia is required.	27
Sympathomimetics (e.g., albuterol, epinephrine)	Mutual antagonism. Landiolol can blunt the therapeutic effects of β-agonists.	Higher doses of the β-agonist may be required. In patients with reactive airway disease, this can be particularly problematic.	1
MAO Inhibitors	Potential for significant and unpredictable hemodynamic instability.	Concurrent use is generally not recommended.	27
Anesthetic Agents (e.g., volatile anesthetics)	May enhance the hypotensive and negative inotropic effects of beta-blockers.	Requires careful titration of both agents with close hemodynamic monitoring.	37

V. Comparative Analysis and Therapeutic Context

Landiolol's position in modern cardiovascular therapy is best understood through a direct comparison with its closest pharmacological relative, esmolol, and by defining the specific clinical scenarios where its unique properties offer a distinct advantage.

5.1 Landiolol versus Esmolol: A Head-to-Head Comparison

While both Landiolol and esmolol are classified as ultra-short-acting, intravenous beta-blockers, they possess key differences in their pharmacological and pharmacokinetic profiles that translate into different clinical behaviors. Landiolol can be viewed not as a revolutionary new drug class, but as a targeted refinement of the therapeutic concept pioneered by esmolol. Esmolol was developed to provide a titratable, short-acting beta-blocker, but its primary limitation is its moderate cardioselectivity, which can lead to clinically significant hypotension, particularly in vulnerable patients.[38] Landiolol was developed with a chemical structure that enhances β1-selectivity by nearly an order of magnitude and further shortens the half-life, directly addressing the clinical limitations encountered with esmolol.[8] This makes Landiolol a superior choice in situations where hemodynamic stability is the paramount concern.

Pharmacodynamic Differences

• Cardioselectivity: This is the most significant differentiator. Landiolol is approximately eight times more selective for the β1-receptor than esmolol, with a selectivity ratio of 255:1 compared to esmolol's ~33:1.[2] This superior selectivity is the primary reason for its more favorable hemodynamic profile.
• Inotropic and Chronotropic Effects: Clinical and preclinical data suggest a dissociation of effects. Landiolol appears to have a more potent negative chronotropic effect (heart rate reduction) for a given dose, while exhibiting a weaker negative inotropic effect (depression of contractility) than esmolol.[9] A retrospective, propensity score-matched study involving 438 ICU patients found that Landiolol achieved a statistically greater reduction in heart rate over 72 hours compared to esmolol.[32]
• Hemodynamic Stability: The higher cardioselectivity and weaker negative inotropy of Landiolol consistently result in less hypotension compared to esmolol. A study in healthy volunteers demonstrated that while both drugs lowered systolic blood pressure, the duration of the hypotensive effect was significantly longer with esmolol.[41] A clinical trial in patients undergoing vascular surgery found a 60% incidence of hypotension in the esmolol group versus 0% in the Landiolol group.[39] The ICU study also found that Landiolol provided superior heart rate control without increasing the need for vasopressors compared to esmolol.[32]

Pharmacokinetic Differences

• Elimination Half-Life: Landiolol has a shorter elimination half-life of approximately 3 to 4 minutes, compared to approximately 9 minutes for esmolol.[4] This allows for even more rapid titration and a faster offset of effect upon discontinuation, providing an additional margin of safety.
• Metabolism: While both drugs are rapidly hydrolyzed by esterases, a minor difference is that the metabolism of esmolol can produce small amounts of methanol, whereas Landiolol's metabolism does not.[9]

Clinical Outcomes

Direct comparative outcome data is still emerging. The retrospective ICU study not only showed better heart rate control with Landiolol but also found that patients in the Landiolol group had significantly shorter ICU and hospital lengths of stay compared to those treated with esmolol.[32] However, large meta-analyses evaluating beta-blockers (grouping Landiolol and esmolol) in sepsis have not demonstrated a clear mortality benefit, with conflicting results between smaller single-center trials and larger multicenter trials, indicating that more research is needed to define their role in improving survival in this complex condition.[42]

5.2 Unique Therapeutic Niche

Landiolol's unique combination of ultra-short action, high potency, exceptional β1-selectivity, and minimal impact on blood pressure and contractility carves out a specific and important therapeutic niche. It is the preferred agent in clinical scenarios where rapid and precise heart rate control is required in a patient who is hemodynamically fragile, has compromised cardiac function, or is at high risk for hypotension.

Ideal patient profiles for Landiolol include:

• Post-Cardiac Surgery Patients: Patients who develop atrial fibrillation or other SVTs after cardiac surgery often have reduced ventricular function and are on vasopressor support, making them highly susceptible to the hypotensive effects of other rate-control agents.
• Critically Ill Patients with Sepsis: In septic patients with tachyarrhythmias who cannot tolerate a drop in blood pressure, Landiolol offers a means of controlling heart rate while preserving hemodynamic stability.[17]
• Patients with Left Ventricular Dysfunction: In patients with pre-existing heart failure or acute cardiac dysfunction (LVEF <40%), preserving myocardial contractility is paramount. Landiolol's weaker negative inotropic effect makes it a safer choice than less selective beta-blockers in this population.[17]
• Patients with Relative Contraindications to Beta-Blockade: For patients with mild reactive airway disease or peripheral vascular disease, the highest possible degree of β1-selectivity is desired to minimize the risk of off-target β2-mediated adverse effects.

VI. Development History and Regulatory Status

The journey of Landiolol from a novel compound to a globally available critical care medication spans several decades and reflects evolving needs in acute cardiovascular medicine.

6.1 Origin and Development

Landiolol, originally designated ONO-1101, was discovered and developed by the Japanese pharmaceutical company Ono Pharmaceutical Co., Ltd..[2] The synthesis of the molecule was first disclosed in patents filed around 1990.[4] The development was driven by a clear clinical need for a beta-blocker with a faster onset, more precise titratability, and a superior safety profile compared to existing agents for the management of acute, particularly perioperative, tachyarrhythmias.[45]

6.2 Global Regulatory Approvals and Commercialization

Landiolol experienced a staggered, two-decade global rollout, with extensive clinical experience accumulating in Japan and Europe long before its approval in North America. This long gap between its initial approval and its eventual availability in the United States likely reflects a growing recognition of the need for more refined hemodynamic control in an increasingly complex and fragile critical care patient population. The extensive real-world and clinical trial data from Japan and Europe formed a substantial part of the evidence base that ultimately supported its FDA approval.

Timeline of Key Approvals

• Japan (PMDA): Landiolol received its first marketing approval from the Japanese Ministry of Health, Labour and Welfare on July 5, 2002, for the emergency treatment of intraoperative tachyarrhythmias.[4] Over the subsequent years, its label was progressively expanded to include postoperative tachycardia (2006), tachyarrhythmias in patients with deteriorated cardiac function (2013), refractory and fatal arrhythmias (2019), and tachyarrhythmia associated with sepsis (2020).[26]
• Europe (EMA): Landiolol was approved in the European Union in June 2016. The approved indications include supraventricular tachycardia, rapid ventricular rate control in atrial fibrillation/flutter, and non-compensatory sinus tachycardia.[10]
• Canada (Health Canada): The drug was approved in Canada in November 2023 for the treatment of supraventricular tachycardias and non-compensatory sinus tachycardia in the intensive care setting.[4]
• United States (FDA): Landiolol was approved by the FDA on November 22, 2024. The indication is for the short-term reduction of ventricular rate in adults with supraventricular tachycardia, including atrial fibrillation and atrial flutter.[4]

Brand Names

The drug is marketed globally under several brand names, reflecting different regional marketing partners:

• Onoact®: The original brand name used in Japan by Ono Pharmaceutical.[2]
• Rapiblyk®: Used in the United States and Australia (AOP Health).[1]
• Rapibloc®, Raploc®, Landiobloc®, Runrapiq®: A portfolio of brand names used across various European countries (AOP Health / AMOMED Pharma).[38]
• Sibboran®: Used in Canada (trimedic therapeutics inc.).[49]

VII. Conclusion

Landiolol represents a significant and refined advancement in the class of beta-adrenergic antagonists, specifically engineered for the acute care environment. Its molecular structure, featuring a labile ester moiety and a pure S-enantiomer configuration, endows it with a unique and highly advantageous pharmacological profile. The confluence of ultra-short-acting pharmacokinetics, with an elimination half-life of approximately four minutes, and exceptional pharmacodynamics, characterized by high potency and the highest β1-receptor selectivity among clinically available beta-blockers (255:1), sets it apart from previous agents.

The most critical clinical feature of Landiolol is its ability to dissociate potent negative chronotropic effects from significant negative inotropic and hypotensive effects. This allows for rapid, effective, and titratable control of ventricular rate in tachyarrhythmias with superior hemodynamic stability compared to its primary comparator, esmolol, and other conventional beta-blockers. This profile makes it an invaluable therapeutic tool for managing tachyarrhythmias in the most vulnerable patient populations—those who are hemodynamically compromised, have underlying cardiac dysfunction, or are in the immediate postoperative period.

While its role in modifying major outcomes like mortality in complex syndromes such as septic shock remains to be definitively established, its efficacy in achieving its primary physiological goal of heart rate control is undisputed. Landiolol fills a crucial therapeutic niche, offering a higher margin of safety and greater predictability for clinicians managing critically ill patients where precise, second-to-second control of cardiac rhythm is required without compromising systemic perfusion. It stands as a prime example of targeted drug design, providing a specialized solution for complex challenges in cardiovascular critical care.

Works cited

1. Landiolol: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 22, 2025, https://go.drugbank.com/drugs/DB12212
2. Landiolol | 133242-30-5 - ChemicalBook, accessed September 22, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB01011742.htm
3. Landiolol free base | CAS#133242-30-5 | beta-blocker - MedKoo Biosciences, accessed September 22, 2025, https://www.medkoo.com/products/24978
4. Landiolol - New Drug Approvals, accessed September 22, 2025, https://newdrugapprovals.org/2025/04/20/landiolol/
5. landiolol | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 22, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=13192
6. Landiolol hydrochloride - Ono Pharmaceutical - AdisInsight - Springer, accessed September 22, 2025, https://adisinsight.springer.com/drugs/800002380
7. CAS 133242-30-5 Landiolol - Alfa Chemistry, accessed September 22, 2025, https://www.alfa-chemistry.com/cas_133242-30-5.htm
8. Landiolol - Wikipedia, accessed September 22, 2025, https://en.wikipedia.org/wiki/Landiolol
9. Landiolol: pharmacology and its use for rate control in atrial ..., accessed September 22, 2025, https://academic.oup.com/eurheartjsupp/article/20/suppl_A/A1/4794889
10. Public Assessment Report Scientific discussion Rapibloc 300 mg ..., accessed September 22, 2025, https://www.geneesmiddeleninformatiebank.nl/pars/h116682.pdf
11. APPLICATION NUMBER: - 217202Orig1s000 CLINICAL PHARMACOLOGY REVIEW(S) - accessdata.fda.gov, accessed September 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/217202Orig1s000ClinPharmR.pdf
12. Landiolol hydrochloride | DrugBank Online, accessed September 22, 2025, https://go.drugbank.com/salts/DBSALT002156
13. What is the mechanism of Landiolol Hydrochloride? - Patsnap Synapse, accessed September 22, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-landiolol-hydrochloride
14. What is Landiolol Hydrochloride used for?, accessed September 22, 2025, https://synapse.patsnap.com/article/what-is-landiolol-hydrochloride-used-for
15. U.S. FDA approves AOP Health's Rapiblyk, accessed September 22, 2025, https://www.aop-health.com/global_en/press/press-releases/us-fda-approves-rapiblyk/
16. (PDF) An Overview of the Pharmacokinetics and Pharmacodynamics of Landiolol (an Ultra-Short Acting β1 Selective Antagonist) in Atrial Fibrillation - ResearchGate, accessed September 22, 2025, https://www.researchgate.net/publication/379661844_An_Overview_of_the_Pharmacokinetics_and_Pharmacodynamics_of_Landiolol_an_Ultra-Short_Acting_b1_Selective_Antagonist_in_Atrial_Fibrillation
17. Landiolol for managing atrial fibrillation in intensive care | European Heart Journal Supplements | Oxford Academic, accessed September 22, 2025, https://academic.oup.com/eurheartjsupp/article/20/suppl_A/A15/4794891
18. RAPIBLYK (landiolol) for injection, for intravenous use - accessdata.fda.gov, accessed September 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217202s000lbl.pdf
19. Landiolol Hydrochloride | American Journal of Health-System Pharmacy - Oxford Academic, accessed September 22, 2025, https://academic.oup.com/ajhp/advance-article/doi/10.1093/ajhp/zxaf018/8046245
20. Summary of Product Characteristics - HPRA, accessed September 22, 2025, https://assets.hpra.ie/products/Human/39199/Licence_PA1353-007-001_15022024134805.pdf
21. Pharmacokinetics of landiolol hydrochloride, a new ultra-short ..., accessed September 22, 2025, https://pubmed.ncbi.nlm.nih.gov/10976545/
22. Efficacy and Safety of Landiolol in the Treatment of Tachycardia in Patients With Sepsis and Septic Shock: A Systematic Review and Meta-Analysis - PMC, accessed September 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12352523/
23. Landiolol (intravenous route) - Side effects & uses - Mayo Clinic, accessed September 22, 2025, https://www.mayoclinic.org/drugs-supplements/landiolol-intravenous-route/description/drg-80002803
24. SUMMARY OF PRODUCT CHARACTERISTICS - Amomed Pharma GmbH, accessed September 22, 2025, https://www.amomed.com/wp-content/uploads/2017/10/ALL_LDL3_Landiolol300mg_SPC.pdf
25. AOP Health Receives Market Authorization for Landiolol in Canada, accessed September 22, 2025, https://www.aop-health.com/global_en/press/press-releases/aop-health-receives-market-authorization-for-landiolol-in-canada/
26. A Short-Acting Selective β1 Blocker, Onoact® for Intravenous ..., accessed September 22, 2025, https://www.ono-pharma.com/sites/default/files/en/news/press/sm_cn200629_2.pdf
27. Landiolol Uses, Side Effects & Warnings - Drugs.com, accessed September 22, 2025, https://www.drugs.com/mtm/landiolol.html
28. FDA Approves Landiolol For Treatment of Supraventricular Tachycardia - Pharmacy Times, accessed September 22, 2025, https://www.pharmacytimes.com/view/fda-approves-landiolol-for-treatment-of-supraventricular-tachycardia
29. Rapiblyk (landiolol) FDA Approval History - Drugs.com, accessed September 22, 2025, https://www.drugs.com/history/rapiblyk.html
30. Announcement of Approval of Additional Indications for Onoact® 50 for Injection, Short-Acting Selective β1 Blocker, accessed September 22, 2025, https://www.ono-pharma.com/sites/default/files/en/news/press/enews20061025.pdf
31. Clinical role and efficacy of landiolol in the intensive care unit - PubMed, accessed September 22, 2025, https://pubmed.ncbi.nlm.nih.gov/18306018/
32. Comparison of the efficacy and safety of Landiolol and Esmolol in critically ill patients: a propensity score-matched study - PMC - PubMed Central, accessed September 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11725550/
33. Landiolol in supraventricular tachycardia: an updated review of clinical applications, accessed September 22, 2025, https://www.ijbcp.com/index.php/ijbcp/article/view/5965
34. Landiolol and Organ Failure in Patients With Septic Shock: The STRESS-L Randomized Clinical Trial, accessed September 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10600724/
35. Atrial Fibrillation Unknown Status Phase Trials for Landiolol (DB12212) | DrugBank Online, accessed September 22, 2025, https://go.drugbank.com/indications/DBCOND0000503/clinical_trials/DB12212?phase=&status=unknown_status
36. Landiolol, an ultra-short acting beta-1 blocker, for preventing postoperative lung cancer recurrence: study protocol for a phase III, multicenter randomized trial with two parallel groups of patients - PubMed Central, accessed September 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6907139/
37. Characteristic interactivity of landiolol, an ultra-short-acting highly selective β1-blocker, with biomimetic membranes - Frontiers, accessed September 22, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2013.00150/full
38. Study into the reversal of septic shock with landiolol (beta blockade): STRESS-L Study protocol for a randomised trial | BMJ Open, accessed September 22, 2025, https://bmjopen.bmj.com/content/11/2/e043194
39. Comparison of Landiolol and Esmolol on Haemodynamic ..., accessed September 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12127960/
40. Comparison of the efficacy and safety of Landiolol and Esmolol in critically ill patients: a propensity score-matched study - PubMed, accessed September 22, 2025, https://pubmed.ncbi.nlm.nih.gov/39800840/
41. Bolus application of landiolol and esmolol: comparison of the pharmacokinetic and pharmacodynamic profiles in a healthy Caucasian group - PubMed, accessed September 22, 2025, https://pubmed.ncbi.nlm.nih.gov/28091703/
42. Mortality in Patients With Sepsis Treated With Esmolol or Landiolol - YouTube, accessed September 22, 2025, https://www.youtube.com/watch?v=3ealZ_OMwYA
43. Mortality in Patients With Sepsis Treated With Esmolol or Landiolol: A Systematic Review and Meta-Analysis of Randomized Controlled Trials With Trial Sequential Analysis - PubMed, accessed September 22, 2025, https://pubmed.ncbi.nlm.nih.gov/39197514/
44. Landiolol: A Review in Tachyarrhythmias - PubMed, accessed September 22, 2025, https://pubmed.ncbi.nlm.nih.gov/29470800/
45. Onoact® 50 for Injection, accessed September 22, 2025, https://www.ono-pharma.com/sites/default/files/en/news/press/enews20020905.pdf
46. Onoact® 50 for Injection, accessed September 22, 2025, https://www.ono-pharma.com/sites/default/files/en/news/press/enews20020723.pdf
47. landiolol - Drug Central, accessed September 22, 2025, https://drugcentral.org/drugcard/1545
48. Landiolol is effective and safe in paediatric supraventricular tachycardia: evidence from a European prospective multicentre open-label phase III study (LANDI-PED) | EP Europace | Oxford Academic, accessed September 22, 2025, https://academic.oup.com/europace/article/27/2/euaf025/8011531
49. Landiolol Hydrochloride | MedPath, accessed September 22, 2025, https://trial.medpath.com/drug/2d6846a8321e5666/landiolol-hydrochloride
50. landiolol: List of nationally authorised medicinal products; PSUSA ..., accessed September 22, 2025, https://www.ema.europa.eu/en/documents/psusa/landiolol-list-nationally-authorised-medicinal-products-psusa00010570201708_en.pdf
51. EMEA-001150-PIP02-13-M05 - paediatric investigation plan - European Medicines Agency, accessed September 22, 2025, https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-001150-pip02-13-m05