Comprehensive Monograph: Metoprolol (DB00264)

Executive Summary

Metoprolol is a cornerstone therapeutic agent in cardiovascular medicine, classified as a beta-1 selective adrenoceptor antagonist.[1] Its primary mechanism of action involves the competitive blockade of beta-1 adrenergic receptors, which are predominantly located in cardiac tissue. This action results in a reduction of heart rate, myocardial contractility, and cardiac output, leading to a decrease in blood pressure and myocardial oxygen demand.[3]

The U.S. Food and Drug Administration (FDA) has approved metoprolol for a range of critical cardiovascular indications, including the management of hypertension, the long-term treatment of angina pectoris, the improvement of survival following an acute myocardial infarction (MI), and as an essential component in the management of stable, symptomatic heart failure.[5] Its clinical utility extends to several off-label uses, such as the control of arrhythmias, migraine prophylaxis, and symptomatic management of thyrotoxicosis.[8]

A defining characteristic of metoprolol therapy is the existence of two principal salt forms with distinct pharmacokinetic profiles and clinical applications: metoprolol tartrate and metoprolol succinate. Metoprolol tartrate (e.g., Lopressor) is an immediate-release (IR) formulation typically administered twice daily, while metoprolol succinate (e.g., Toprol-XL, Kapspargo Sprinkle) is an extended-release (ER) formulation designed for once-daily administration.[10] This distinction is not merely a matter of dosing convenience; it is fundamental to the drug's application. The ER formulation's ability to provide stable 24-hour beta-blockade is critical for its proven mortality benefit in chronic heart failure, an indication for which the IR form is not specifically approved.[11] Consequently, these formulations are not interchangeable, and the selection of the appropriate salt form is a crucial clinical decision.

The metabolism of metoprolol is predominantly mediated by the hepatic enzyme cytochrome P450 2D6 (CYP2D6).[4] This enzyme is subject to significant genetic polymorphism, leading to wide inter-individual variability in drug clearance. Individuals classified as "poor metabolizers" may experience substantially elevated plasma concentrations and an increased risk of adverse effects with standard doses. Furthermore, the co-administration of drugs that inhibit CYP2D6 can phenotypically convert a normal metabolizer into a poor metabolizer, amplifying the potential for drug-drug interactions.[4] This metabolic pathway underscores the necessity for careful dose titration and vigilant monitoring in clinical practice.

Chemical Identity and Pharmaceutical Formulations

The precise identification and understanding of metoprolol's chemical properties and available formulations are essential for its safe and effective use.

Nomenclature, Identifiers, and Physicochemical Properties

Metoprolol is a synthetic compound belonging to the propanolamine class of beta-adrenergic antagonists.[1]

• Chemical Name: The International Union of Pure and Applied Chemistry (IUPAC) name for metoprolol is 1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol.[1]
• Chemical Class: It is structurally classified as a propanolamine, an aromatic ether, a secondary alcohol, and a secondary amino compound.[1]
• Key Identifiers:
• DrugBank ID: DB00264 [1]
• CAS Number: 51384-51-1 [1]
• Molecular Formula: C15​H25​NO3​ [16]
• Molecular Weight: 267.36 g/mol [1]
• Physicochemical Properties: Metoprolol base is a white to off-white, practically odorless, crystalline powder.[4] The tartrate salt form is highly soluble in water (>1000 mg/mL), methanol, and chloroform, but sparingly soluble in acetone and practically insoluble in hexane.[1] Key experimental properties include a melting point of approximately 120 °C and an estimated boiling point of 398 °C.[1] Its partition coefficient (LogP) values range from 1.88 to 2.15, indicating moderate lipophilicity.[1]

Stereochemistry and Salt Forms: Tartrate, Succinate, and Fumarate

Metoprolol possesses a chiral center and is clinically administered as a racemic mixture of its (R)- and (S)-enantiomers.[4] The beta-1 blocking activity resides almost exclusively in the (S)-enantiomer, while the (R)-enantiomer is largely inactive.[13] The drug is available in several salt forms, which dictate its formulation and pharmacokinetic properties.

• Metoprolol Tartrate: This salt form is used in immediate-release (IR) tablets (brand name Lopressor) and for intravenous (IV) solutions.[3] The molecular weight of the metoprolol tartrate salt (2:1 drug-to-tartrate ratio) is 684.82 g/mol.[4] Its chemical structure is formally described as (±)-1-(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt.[4]
• Metoprolol Succinate: This salt is specifically used to create extended-release (ER) formulations (brand names Toprol-XL, Kapspargo Sprinkle) that allow for consistent drug delivery over a 24-hour period, enabling once-daily dosing.[1]
• Metoprolol Fumarate: A fumarate salt form has also been developed (e.g., Lopressor OROS), though it is less commonly encountered in clinical practice than the tartrate and succinate forms.[20]

Available Formulations, Strengths, and Brand Names

The diversity of metoprolol formulations necessitates precise prescribing and dispensing to ensure the correct product is used for the intended indication. The tartrate and succinate forms are not interchangeable.[11]

• Immediate-Release (IR) Tablets (Metoprolol Tartrate):
• Brand Name: Lopressor, Metoprolol Tartrate [16]
• Strengths: 25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg [10]
• Extended-Release (ER) Tablets (Metoprolol Succinate):
• Brand Name: Toprol-XL, Metoprolol Succinate ER [11]
• Strengths: 25 mg, 50 mg, 100 mg, 200 mg [26]
• Administration Note: These tablets are scored and can be split in half, but they must not be chewed or crushed.[28]
• Extended-Release (ER) Capsules (Metoprolol Succinate):
• Brand Name: Kapspargo Sprinkle [16]
• Strengths: 25 mg, 50 mg, 100 mg, 200 mg [11]
• Administration Note: Designed for patients with dysphagia, the capsule can be opened and the contents sprinkled onto soft food (e.g., applesauce, yogurt) for immediate consumption.[5]
• Intravenous (IV) Solution (Metoprolol Tartrate):
• Brand Name: Lopressor Injection [26]
• Strength: 1 mg/mL [26]
• Use: Primarily in acute hospital settings, such as for the early treatment of MI.[3]
• Oral Solution (Metoprolol Tartrate):
• Brand Name: Lopressor [27]
• Strength: 10 mg/mL [27]
• Combination Products:
• Product: Metoprolol Tartrate/Hydrochlorothiazide [16]
• Brand Names: Lopressor HCT, Dutoprol [16]
• Use: Management of hypertension.[16]
• International Brand Names: In addition to the U.S. brand names, metoprolol is marketed globally under various names, including Beloc, Betaloc, Seloken, and Selo-Zok.[22]

The clear distinction between metoprolol tartrate (IR) and metoprolol succinate (ER) is a critical point of potential clinical error. An accidental switch could lead to sub-therapeutic effects, such as a loss of 24-hour blood pressure control, or unexpected peak-dose side effects. A clinician or pharmacist requires a clear understanding to ensure the correct product is selected, especially when transitioning a patient from an inpatient setting (often using IV tartrate) to an outpatient regimen. The following table provides a quick-reference tool to consolidate this information and enhance patient safety.

Table 1: Metoprolol Formulations and Brand Names

Salt Form	Release Mechanism	U.S. Brand Name(s)	Common International Brand Names	Available Dosage Forms	Available Strengths
Metoprolol Tartrate	Immediate-Release (IR)	Lopressor, Metoprolol Tartrate	Betaloc, Seloken	Tablet	25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg
		Lopressor		Oral Solution	10 mg/mL
		Lopressor Injection		Intravenous Solution	1 mg/mL
Metoprolol Succinate	Extended-Release (ER)	Toprol-XL, Metoprolol Succinate ER	Beloc-Zok, Selo-Zok	Tablet	25 mg, 50 mg, 100 mg, 200 mg
		Kapspargo Sprinkle		Capsule (sprinkle)	25 mg, 50 mg, 100 mg, 200 mg
Metoprolol Tartrate / Hydrochlorothiazide	Immediate-Release (IR)	Lopressor HCT, Dutoprol		Combination Tablet	Varies

Clinical Pharmacology

The therapeutic effects of metoprolol are a direct result of its specific interactions with the adrenergic nervous system and its subsequent journey through the body. A thorough understanding of its pharmacodynamics and pharmacokinetics is crucial for optimizing therapy.

Pharmacodynamics: The Mechanism of Selective Beta-1 Adrenergic Blockade

Metoprolol is classified as a beta-1 selective (cardioselective) adrenergic receptor blocking agent.[3] Its primary therapeutic action is the competitive antagonism of beta-1 adrenoceptors, which are found in high density in the cardiac muscle.[3] This blockade of endogenous catecholamines (e.g., epinephrine, norepinephrine) at cardiac receptor sites produces several key hemodynamic effects:

• Negative Chronotropy: A reduction in heart rate, both at rest and during physical exertion.[3]
• Negative Inotropy: A decrease in the force of myocardial contraction.[3]
• Reduced Cardiac Output: The combined effects on heart rate and contractility lead to a decrease in the total volume of blood pumped by the heart per minute.[4]
• Antihypertensive Effect: The precise mechanism for lowering blood pressure has not been fully elucidated but is attributed to several factors: the reduction in cardiac output, a central effect leading to reduced sympathetic outflow from the brain to the periphery, and suppression of renin release from the kidneys.[4]

In the context of angina pectoris, by attenuating the heart's response to sympathetic stimulation, metoprolol reduces myocardial oxygen consumption at any given level of effort. This rebalances the myocardial oxygen supply-demand equation, resulting in fewer anginal episodes and improved exercise capacity.[3]

It is critical to recognize that this beta-1 selectivity is relative and dose-dependent. At higher plasma concentrations, metoprolol loses its selectivity and can also inhibit beta-2 adrenoceptors, which are located primarily in the bronchial and vascular smooth muscle.[4] Blockade of these receptors can interfere with bronchodilation, potentially precipitating bronchospasm in susceptible patients, such as those with asthma.[9]

Pharmacokinetics: A Comparative Analysis

The absorption, distribution, metabolism, and excretion (ADME) profile of metoprolol, particularly its reliance on a specific metabolic pathway, dictates its clinical behavior.

Absorption, Distribution, Metabolism, and Excretion (ADME)

• Absorption: Following oral administration, metoprolol is rapidly and almost completely absorbed from the gastrointestinal tract, with over 90% absorption.[31] However, it is subject to extensive first-pass metabolism in the liver, which removes a significant fraction of the drug before it reaches systemic circulation. This effect reduces its absolute oral bioavailability to approximately 40-50%.[19] The presence of food can increase the absorption of the immediate-release tartrate formulation.[31] Peak plasma concentrations are typically reached 1 to 2 hours after an oral dose of the IR formulation.[31]
• Distribution: Metoprolol is widely distributed throughout the body, with a large volume of distribution reported between 3.2 and 5.6 L/kg.[4] Plasma protein binding is low, at approximately 10-12%, primarily to serum albumin.[4] Due to its moderate lipophilicity, metoprolol crosses the blood-brain barrier, which accounts for its central nervous system effects and efficacy in migraine prophylaxis. It also crosses the placental barrier and is excreted into breast milk in small amounts.[4]
• Metabolism: Metoprolol undergoes extensive hepatic metabolism, with the liver transforming about 95% of the absorbed dose.[13] The primary metabolic pathways are O-demethylation (accounting for ~65% of metabolism) and alpha-hydroxylation (~10%), followed by N-dealkylation (~10%).[13] These processes generate several metabolites. The O-demethylated product is rapidly oxidized to metoprolol acid, an inactive metabolite that is the main form found in urine. The alpha-hydroxymetoprolol metabolite is pharmacologically active but possesses only about one-tenth the beta-blocking potency of the parent compound.[13]
• Excretion: The metabolites of metoprolol are primarily eliminated by the kidneys. Approximately 95% of an administered dose is recovered in the urine, with less than 5% excreted as unchanged parent drug.[13] The typical elimination half-life is 3 to 4 hours in individuals with normal metabolic function.[4]

The Critical Role of CYP2D6 and Genetic Polymorphisms

The biotransformation of metoprolol is critically dependent on the cytochrome P450 enzyme system, specifically the CYP2D6 isoenzyme.[4] This enzyme is well-known for its genetic polymorphism, which results in distinct population phenotypes for drug metabolism.

Approximately 8% of Caucasians and 2% of most other populations are classified as "poor metabolizers" (PMs) because they lack functional CYP2D6 enzymes.[4] In these individuals, the clearance of metoprolol is significantly reduced, and the elimination half-life can be prolonged to 7 to 9 hours.[4] This leads to substantially higher plasma concentrations from a standard dose, increasing the risk of exaggerated pharmacologic effects and adverse events like severe bradycardia and hypotension. In contrast, "extensive metabolizers" (EMs) have normal enzyme function and the expected 3-4 hour half-life.[4]

This pharmacogenetic variability is a central, yet often underappreciated, driver of the wide inter-individual differences observed in metoprolol's efficacy and toxicity. A significant portion of the population is either genetically a poor metabolizer or can become a "phenotypic" poor metabolizer through the co-administration of potent CYP2D6-inhibiting drugs, such as the antidepressants fluoxetine and paroxetine, the antiarrhythmic quinidine, or the antihistamine diphenhydramine.[14] These inhibitors can effectively double metoprolol concentrations, creating a similar risk profile to that of a genetic PM.[14] This complex interplay explains the common clinical observation of why some patients on a low dose of metoprolol develop profound fatigue and bradycardia, while others on the maximum dose fail to achieve adequate therapeutic response. It transforms the drug from a "one-size-fits-all" medication into one that requires highly individualized management, necessitating slow and careful dose titration based on clinical response and tolerance.

Pharmacokinetic Profiles: Immediate-Release (Tartrate) vs. Extended-Release (Succinate)

The choice of salt form directly impacts the drug's pharmacokinetic profile and dosing regimen.

• Metoprolol Tartrate (IR): This formulation leads to rapid absorption and a pronounced peak in plasma concentration. While this produces a significant peak effect on heart rate reduction, the effect wanes and is often not evident at the end of a 24-hour dosing interval.[12] This pharmacokinetic profile necessitates twice-daily administration to maintain therapeutic beta-blockade throughout the day.[11]
• Metoprolol Succinate (ER): This advanced formulation consists of a multiple-unit pellet system, where each pellet acts as a separate controlled-release unit.[12] This design provides a controlled and predictable release of metoprolol over approximately 24 hours, resulting in a much smoother plasma concentration curve that avoids the sharp peaks and deep troughs associated with the IR form. While providing comparable total beta-1 blockade over a 24-hour period, its stable profile is particularly advantageous for the chronic management of conditions like heart failure and hypertension, allowing for effective once-daily administration.[11]

Therapeutic Applications and Clinical Efficacy

Metoprolol has a broad range of applications in cardiovascular medicine, supported by extensive clinical trial data. Its uses span from the management of chronic conditions to acute, life-threatening events.

Management of Hypertension

Metoprolol is an FDA-approved agent for the treatment of hypertension, where it can be used as monotherapy or in combination with other antihypertensive drugs.[5] Its efficacy in lowering both systolic and diastolic blood pressure has been consistently demonstrated in clinical studies.[3] The primary benefit of treating hypertension is the reduction in the risk of fatal and non-fatal cardiovascular events, with the most consistent outcome benefit being a reduction in the risk of stroke, alongside reductions in myocardial infarction and cardiovascular mortality.[6] In controlled trials, metoprolol has shown antihypertensive efficacy comparable to other established agents like propranolol, methyldopa, and thiazide-type diuretics.[3] However, contemporary treatment guidelines often recommend other classes, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), or calcium channel blockers, as first-line therapy, with the choice depending on patient characteristics like age, ethnicity, and comorbidities.[37]

Long-Term Treatment of Angina Pectoris

The FDA has approved metoprolol for the long-term management of angina pectoris.[5] By blocking catecholamine-induced increases in heart rate and contractility, metoprolol effectively reduces myocardial oxygen demand.[3] This action helps to alleviate the imbalance between oxygen supply and demand in the heart muscle that causes ischemic chest pain. Clinically, this translates to a reduction in the frequency of angina attacks and an improvement in exercise tolerance, allowing patients to engage in more physical activity before experiencing symptoms.[3] Clinical trials have established the efficacy of daily doses ranging from 100 mg to 400 mg for this indication.[3]

Acute Myocardial Infarction (MI) and Secondary Prevention

Metoprolol plays a crucial role in the management of patients with a definite or suspected acute myocardial infarction. It is FDA-approved to reduce cardiovascular mortality and improve survival in this setting.[5] Treatment is typically initiated in hemodynamically stable patients, often beginning with an intravenous loading dose in the hospital, followed by a transition to a regular oral maintenance regimen.[6] A landmark, large-scale, placebo-controlled clinical study demonstrated that metoprolol reduced 3-month mortality by 36% in patients following an MI.[3] In addition to its mortality benefit, metoprolol has also been shown to significantly reduce the incidence of life-threatening ventricular fibrillation post-infarction.[3]

Management of Stable, Symptomatic Heart Failure (NYHA Class II-III)

The use of metoprolol in heart failure represents a significant evolution in cardiovascular therapy. Initially, beta-blockers were considered contraindicated in heart failure due to their negative inotropic effects, with the belief that they would worsen cardiac function.[3] However, this long-held dogma was overturned by rigorous clinical trials. Specifically, the extended-release formulation, metoprolol succinate (Toprol-XL), is FDA-approved for the treatment of stable, symptomatic heart failure (New York Heart Association Class II or III) of ischemic, hypertensive, or cardiomyopathic origin.[5]

It is used as an adjunct to standard heart failure therapies, such as ACE inhibitors and diuretics.[7] The mechanism is thought to involve protecting the heart from the chronic cardiotoxic effects of elevated catecholamine levels, thereby preventing adverse cardiac remodeling. Clinical evidence demonstrates that metoprolol succinate improves overall survival, reduces the rate of hospitalization for heart failure, enhances left ventricular ejection fraction, and delays the progression of left ventricular enlargement.[7] Therapy must be initiated cautiously at a very low dose (e.g., 12.5 mg or 25 mg once daily) and titrated upwards slowly over a period of several weeks to the target dose of 200 mg daily, as tolerated by the patient.[26] This careful, gradual approach is critical to avoid acute decompensation. This paradigm shift underscores the importance of formulation (ER being essential for this indication) and evidence-based medicine in modern cardiology.

Off-Label and Ancillary Uses

Beyond its FDA-approved indications, metoprolol is widely used for several off-label conditions:

• Cardiac Arrhythmias: It is frequently used for rate control in patients with atrial fibrillation or atrial flutter and for the treatment of other supraventricular tachycardias.[5]
• Migraine Prophylaxis: Metoprolol is an established preventive therapy for migraine headaches, reducing the frequency and severity of attacks.[7]
• Thyrotoxicosis: It is used as an adjunctive therapy to control the adrenergic symptoms of hyperthyroidism, such as tachycardia, palpitations, and tremor, while awaiting definitive treatment of the thyroid disorder.[8]
• Other Documented Uses: Additional off-label applications include the management of benign essential tremor, hypertrophic cardiomyopathy, aortic dissection, and certain ventricular arrhythmias.[9]

Dosing, Administration, and Therapeutic Monitoring

The successful application of metoprolol therapy depends on appropriate dosing, correct administration, and diligent monitoring tailored to the specific patient and clinical indication.

Indication-Specific Dosing Regimens

Dosing for metoprolol is highly variable and must be individualized based on the patient's condition and the specific formulation being used. The starting doses for heart failure are substantially lower than those for hypertension, highlighting the need for precise prescribing.

• Hypertension:
• Metoprolol Tartrate (IR): The typical starting dosage is 100 mg per day, administered as a single dose or in two divided doses. The dose can be titrated upwards at weekly or longer intervals to a maintenance range of 100 to 450 mg per day.[6]
• Metoprolol Succinate (ER): The initial dosage is 25 to 100 mg once daily. The dose may be increased as needed to a maximum of 400 mg per day.[27]
• Angina Pectoris:
• Metoprolol Tartrate (IR): The recommended starting dosage is 100 mg per day, given in two divided doses (50 mg twice daily). The dose can be titrated weekly up to a total daily dose of 400 mg.[6]
• Metoprolol Succinate (ER): The usual initial dosage is 100 mg once daily, which can be titrated up to a maximum of 400 mg per day.[26]
• Acute Myocardial Infarction:
• Early Treatment (In-hospital): Therapy often begins with intravenous metoprolol tartrate, administered as three 5 mg bolus injections at 2-minute intervals. For patients who tolerate the full 15 mg IV dose, oral therapy with metoprolol tartrate 50 mg every 6 hours is initiated 15 minutes after the last IV dose and continued for 48 hours. This is followed by a maintenance dosage of 100 mg orally twice daily.[26]
• Heart Failure (Stable, Symptomatic):
• Metoprolol Succinate (ER): This is the only formulation indicated for heart failure. Treatment must start at a low dose. The recommended initial dose is 25 mg once daily for most patients, or 12.5 mg once daily for those with more severe heart failure. The dose should be doubled every two weeks, as tolerated, to the highest tolerated dose or up to the target dosage of 200 mg once daily.[26]

Guidelines for Administration and Titration

To ensure consistent absorption and minimize variability, metoprolol should be taken with a meal or immediately following a meal.[5] Dose titration should be performed gradually, typically at intervals of one week or longer for hypertension and angina, and at two-week intervals for heart failure.[6] This allows the full hemodynamic effect of a given dose to be realized before further adjustments are made.

Transitioning Between Formulations

Switching between metoprolol formulations requires clinical oversight. The IR and ER products are not therapeutically equivalent on a milligram-for-milligram basis due to their distinct pharmacokinetic profiles, and a direct conversion is not recommended without a new prescription and clinical assessment.[11] A common transition occurs in post-MI patients, who are moved from IV metoprolol tartrate to oral metoprolol tartrate in the hospital.[27] If a long-term transition to the once-daily succinate form is desired, this must be managed as a new prescription with appropriate dose selection.

Essential Monitoring Parameters

Regular and targeted monitoring is essential to ensure efficacy and safety.

• Efficacy Monitoring:
• Hypertension: Blood pressure should be checked regularly to assess response to therapy.[5]
• Angina: Monitor the frequency and severity of anginal attacks and changes in exercise tolerance.[9]
• Heart Failure: Track patient symptoms such as dyspnea and fatigue, and monitor for signs of fluid retention, including peripheral edema and daily weight changes.[5]
• Safety Monitoring:
• Cardiovascular: Monitor heart rate and, if indicated, ECG to detect excessive bradycardia or heart block.[9]
• Respiratory: Assess for signs of bronchospasm, such as wheezing or coughing, particularly in patients with a history of reactive airway disease.[9]
• General: Be alert for common side effects like dizziness, fatigue, and depression, which may be dose-limiting.[5]

Table 2: Indication-Specific Dosing Regimens for Metoprolol

Indication	Formulation	Initial Dose	Titration Schedule	Maximum / Target Dose
Hypertension	Tartrate (IR)	100 mg/day (single or divided)	Titrate weekly as needed	450 mg/day
	Succinate (ER)	25-100 mg once daily	Titrate weekly as needed	400 mg/day
Angina Pectoris	Tartrate (IR)	50 mg twice daily	Titrate weekly as needed	400 mg/day
	Succinate (ER)	100 mg once daily	Titrate weekly as needed	400 mg/day
Acute MI	Tartrate (IV)	5 mg IV x 3 doses (q2min)	N/A	15 mg total IV dose
	Tartrate (Oral)	50 mg PO q6h for 48h	N/A	100 mg twice daily (maintenance)
Heart Failure	Succinate (ER)	12.5-25 mg once daily	Double dose every 2 weeks	200 mg once daily (target)

Safety Profile and Risk Management

The safety profile of metoprolol is well-characterized and is intrinsically linked to its mechanism of action. The predictable consequences of beta-adrenergic blockade in various physiological contexts form the basis for its warnings, contraindications, and adverse effect profile. Understanding these principles, rather than simply memorizing a list of rules, allows for proactive risk management and safer prescribing.

Adverse Drug Reactions: From Common to Serious

Adverse effects associated with metoprolol range from mild and transient to severe and potentially life-threatening.

• Common Side Effects: The most frequently reported adverse reactions are often related to the drug's primary pharmacologic effects or its ability to cross the blood-brain barrier. These include dizziness or lightheadedness, fatigue, depression, diarrhea, nausea, dry mouth, constipation, and coldness in the hands and feet.[5] These are often dose-dependent and may diminish with time or dose reduction.
• Serious Side Effects: Although less common, serious adverse events require immediate medical attention. These are typically extensions of the drug's beta-blocking activity and include:
• Cardiovascular: Severe bradycardia (abnormally slow heart rate), hypotension (low blood pressure), fainting (syncope), and exacerbation of heart failure, indicated by shortness of breath, wheezing, swelling of the lower extremities (edema), and rapid weight gain.[5]
• Respiratory: Bronchospasm, particularly in patients with pre-existing asthma or bronchospastic disease.[6]
• Psychiatric: Severe depression with symptoms of hopelessness or loss of interest in hobbies.[10]

Boxed Warning: Ischemic Heart Disease Following Abrupt Cessation

Metoprolol carries a prominent FDA Boxed Warning regarding the dangers of abrupt discontinuation.[6] Suddenly stopping therapy, especially in patients with underlying coronary artery disease, can lead to a withdrawal syndrome characterized by worsening angina pectoris, myocardial infarction, and ventricular arrhythmias.[5]

The underlying mechanism for this phenomenon is receptor upregulation. Chronic blockade of beta-1 receptors leads the body to increase the number and sensitivity of these receptors on cell surfaces. When the blocking agent is suddenly removed, endogenous catecholamines (like adrenaline) encounter an overabundance of available receptors, triggering a hypersensitive, exaggerated sympathetic response. This results in rebound tachycardia, increased blood pressure, and heightened myocardial oxygen demand, which can precipitate an ischemic event. To mitigate this risk, the dosage of metoprolol must be tapered gradually over a period of 1 to 2 weeks under close medical supervision.[5]

Contraindications and High-Risk Patient Scenarios

Metoprolol is strictly contraindicated in certain clinical situations where its pharmacologic effects would be overtly harmful:

• Severe Bradycardia, High-Degree Heart Block, or Sick Sinus Syndrome: In patients with significant pre-existing conduction system disease (e.g., second- or third-degree heart block) or profound bradycardia, metoprolol is contraindicated unless a functioning permanent pacemaker is in place. Administering the drug in this context could lead to life-threatening bradyarrhythmias or asystole.[6]
• Cardiogenic Shock or Decompensated Heart Failure: In states of acute cardiac decompensation or shock, where cardiac output is critically dependent on sympathetic drive, the negative inotropic and chronotropic effects of metoprolol can lead to catastrophic hemodynamic collapse.[6]
• Hypersensitivity: A known history of hypersensitivity to metoprolol or any of its components is a contraindication.[6]

Warnings and Precautions

Beyond absolute contraindications, several clinical scenarios require caution and careful risk-benefit assessment:

• Bronchospastic Disease: Due to the risk of beta-2 receptor blockade, beta-blockers are generally avoided in patients with asthma. If metoprolol is deemed necessary, its cardioselectivity makes it a preferable option over non-selective agents. The lowest possible dose should be used, and a beta-2 agonist bronchodilator should be readily available.[6]
• Diabetes Mellitus: Beta-blockers can mask the adrenergic warning signs of hypoglycemia, particularly tachycardia. This can prevent patients from recognizing a developing low blood sugar episode, increasing the risk of severe or prolonged hypoglycemia. Patients with diabetes must be counseled on this risk and advised to monitor their blood glucose levels closely.[5]
• Major Surgery: The continuation or withdrawal of metoprolol prior to major surgery is a complex decision. Chronic therapy should not be routinely withdrawn, but the drug's blockade of adrenergic responses can impair the heart's ability to compensate for the stresses of general anesthesia and surgical procedures, potentially increasing risks.[5]
• Pheochromocytoma: In patients with this catecholamine-secreting tumor, administering a beta-blocker alone can lead to a paradoxical and severe hypertensive crisis. This occurs because blocking beta-2-mediated vasodilation leaves alpha-1-mediated vasoconstriction unopposed. Therefore, metoprolol must only be given after alpha-adrenergic blockade has been established.[6]
• Thyrotoxicosis: Metoprolol can mask the clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal in a patient with an underlying thyroid disorder could precipitate a life-threatening thyroid storm.[6]
• Peripheral Vascular Disease: Beta-blockers can reduce peripheral blood flow and may precipitate or aggravate the symptoms of arterial insufficiency in patients with conditions like Raynaud's phenomenon.[6]

Toxicology and Management of Overdose

An overdose of metoprolol can result in severe toxicity. The primary manifestations include profound hypotension, sinus bradycardia, atrioventricular (AV) block, cardiogenic shock, and cardiac arrest. Other symptoms may include bronchospasm, impaired consciousness, coma, nausea, and vomiting.[5] Management is primarily supportive and aimed at reversing the effects of beta-blockade. Standard interventions may include intravenous fluids, atropine for bradycardia, vasopressors (e.g., norepinephrine) for hypotension, and in severe cases, intravenous glucagon, which can increase heart rate and contractility via a mechanism that is independent of beta-receptors.

Clinically Significant Interactions

Metoprolol is subject to a large number of drug interactions, with over 500 documented.[41] These can be broadly categorized by their mechanism: pharmacokinetic interactions that alter drug levels and pharmacodynamic interactions that result in additive or antagonistic effects. A prioritized, mechanism-based understanding is essential for safe co-prescribing.

Pharmacokinetic Interactions: The CYP2D6 Pathway

The most significant pharmacokinetic interactions involve the CYP2D6 metabolic pathway. As metoprolol is a primary substrate of this enzyme, co-administration with drugs that inhibit CYP2D6 can lead to a clinically meaningful increase in metoprolol plasma concentrations, thereby potentiating its effects and increasing the risk of adverse events like bradycardia and hypotension.[14]

• Strong CYP2D6 Inhibitors: Potent inhibitors can double metoprolol concentrations and should be used with extreme caution or avoided. If co-administration is necessary, a reduction in the metoprolol dose and close monitoring are required. Key drugs in this category include:
• Antidepressants: Fluoxetine, paroxetine, bupropion.[14]
• Antiarrhythmics: Quinidine, propafenone.[13]
• Antihistamines: Diphenhydramine.[34]
• Other: Terbinafine, mavorixafor (contraindicated).[27]
• Moderate and Weak Inhibitors: Drugs like abiraterone and others can also increase metoprolol levels, warranting increased vigilance and potential dose adjustments.[14]

Pharmacodynamic Interactions: Additive and Antagonistic Effects

These interactions occur when two drugs have complementary or opposing effects at the receptor or system level.

• Additive Bradycardic and Hypotensive Effects: The risk of excessive heart rate slowing and/or hypotension is increased when metoprolol is combined with other drugs that have similar effects.
• Calcium Channel Blockers (Non-dihydropyridine): Verapamil and diltiazem have their own negative chronotropic and inotropic effects. Their combination with metoprolol can lead to severe bradycardia and AV block.[14]
• Digitalis Glycosides: Digoxin slows AV conduction, and its use with metoprolol can result in an additive effect, increasing the risk of bradycardia.[10]
• Other Antihypertensives: Co-administration with clonidine requires careful management, as the rebound hypertension that can occur upon clonidine withdrawal may be exacerbated by beta-blockade.[10] Catecholamine-depleting drugs (e.g., reserpine) and Monoamine Oxidase Inhibitors (MAOIs) can also have additive hypotensive and bradycardic effects.[14]
• Antagonistic Effects:
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Drugs like ibuprofen and naproxen can antagonize the antihypertensive effect of metoprolol, potentially by inhibiting renal prostaglandin synthesis and causing sodium and water retention. This can lead to an increase in blood pressure.[42]
• Beta-2 Adrenergic Agonists: Bronchodilators such as albuterol, used to treat asthma, work by stimulating beta-2 receptors. Metoprolol, especially at higher doses, can block these receptors and blunt the therapeutic effect of the bronchodilator.[12]

Drug-Food and Drug-Lifestyle Interactions

• Food: It is recommended to take metoprolol with food or immediately after a meal. Food can enhance the absorption of the drug, particularly the immediate-release tartrate formulation, leading to higher and more consistent bioavailability.[31]
• Sodium: A diet high in sodium can increase fluid retention and blood pressure, thereby counteracting the therapeutic effect of metoprolol. Patients are often advised to follow a low-sodium diet, such as the DASH (Dietary Approaches to Stop Hypertension) diet.[33]
• Caffeine: Excessive consumption of caffeine can raise blood pressure and heart rate, potentially diminishing the effectiveness of metoprolol.[33]
• Alcohol: Alcohol can have an additive blood pressure-lowering effect when combined with metoprolol, which may increase the risk of dizziness, lightheadedness, and syncope.[33]

Table 3: Clinically Significant Drug Interactions with Metoprolol

Interacting Drug/Class	Mechanism of Interaction	Potential Clinical Effect	Management Recommendation
Fluoxetine, Paroxetine, Quinidine, Diphenhydramine	Pharmacokinetic (PK): Strong CYP2D6 Inhibition	Increased metoprolol concentration; risk of profound bradycardia, hypotension	Avoid combination if possible. If necessary, use a significantly reduced metoprolol dose and monitor closely.
Verapamil, Diltiazem	Pharmacodynamic (PD): Additive Negative Chronotropic/Inotropic Effects	Severe bradycardia, AV block, heart failure exacerbation	Combination should be used with extreme caution and requires close cardiac monitoring.
Digoxin	PD: Additive Effect on AV Conduction	Increased risk of bradycardia and heart block	Monitor heart rate and ECG. Dose adjustments may be necessary.
Clonidine	PD: Exacerbation of Rebound Hypertension	Severe rebound hypertension upon clonidine withdrawal	Withdraw metoprolol several days before gradually withdrawing clonidine.
NSAIDs (e.g., Ibuprofen)	PD: Antagonism of Antihypertensive Effect	Reduced blood pressure control, fluid retention	Limit or avoid concurrent use of NSAIDs. Monitor blood pressure closely.
Beta-2 Agonists (e.g., Albuterol)	PD: Antagonism of Bronchodilator Effect	Reduced efficacy of asthma/COPD treatment	Use with caution, especially at higher metoprolol doses. Monitor respiratory status.
MAO Inhibitors	PD: Additive Hypotensive Effect	Significant hypotension and bradycardia	Use combination with caution and monitor for evidence of hypotension.

Use in Special Populations

The pharmacokinetic and pharmacodynamic properties of metoprolol necessitate special consideration when used in specific patient populations, including the elderly, children, pregnant or lactating women, and those with organ dysfunction. The primary determinant for dose adjustment in these groups is most often hepatic function, not renal function.

Geriatric Considerations: Dosing, Sensitivity, and Tapering

Elderly patients often exhibit altered drug handling compared to younger adults. They may show slightly higher plasma concentrations of metoprolol, which is attributed to an age-related decrease in hepatic metabolism and reduced hepatic blood flow.[44] Consequently, a general principle is to "start low and go slow," initiating therapy with a low dose and titrating gradually based on clinical response.[44] For hypertension, studies have found that an initial dose of 100 mg daily is often effective and well-tolerated.[45]

Geriatric patients are also more susceptible to adverse effects, particularly orthostatic hypotension, dizziness, and neuropsychiatric side effects like confusion, depression, and sleep disturbances, which can occur even at low doses.[45] The risk associated with abrupt withdrawal is heightened in this population due to reduced physiological reserve. A gradual dose taper over several weeks, reducing the dose by 25-50% every 1 to 2 weeks with close monitoring of heart rate and blood pressure, is crucial to prevent rebound cardiac events.[44]

Pediatric Use in Hypertension

The extended-release formulation of metoprolol succinate is FDA-approved for the treatment of hypertension in children aged 6 years and older.[27] The dosage is based on body weight. The recommended starting dose is 1 mg/kg once daily, with the initial dose not to exceed 50 mg per day.[38] The dose can be titrated upwards according to blood pressure response to a maximum dose of 2 mg/kg or 200 mg once daily.[39] Close monitoring of heart rate and blood pressure is essential during therapy.[28]

Use During Pregnancy and Lactation

• Pregnancy: Metoprolol is assigned FDA Pregnancy Category C, indicating that animal studies have shown adverse effects, but there are no adequate and well-controlled studies in humans. It should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.[47] Use of metoprolol during pregnancy may be associated with fetal growth restriction, and additional ultrasound monitoring may be recommended.[48] There is also a potential risk for neonatal side effects, including bradycardia and hypoglycemia. Therefore, if metoprolol is used near term, the newborn should be monitored for these effects for the first 48-72 hours after birth.[49]
• Lactation: Metoprolol is considered compatible with breastfeeding.[48] The drug is excreted into breast milk, but in very small quantities. It is estimated that a fully breastfed infant would receive a dose of less than 1 mg per day, which is less than 1% of the maternal weight-adjusted dose.[49] Adverse effects in breastfed infants have not been reported in studies, but it is still prudent to monitor the infant for any signs of beta-blockade, such as unusual sleepiness, listlessness, or poor feeding.[48]

Patients with Hepatic and Renal Impairment

• Hepatic Impairment: Since metoprolol is cleared almost entirely by hepatic metabolism, its clearance is significantly reduced in patients with liver disease. Hepatic impairment can lead to substantially increased blood levels and a prolonged elimination half-life.[27] Therefore, patients with hepatic dysfunction should be started on a low dose of metoprolol, and titration should proceed slowly and cautiously according to clinical response.[40]
• Renal Impairment: The pharmacokinetics of metoprolol and its metabolites are not significantly altered in patients with renal failure. Consequently, dosage adjustments are generally not required, even in patients with severe chronic renal failure or those on dialysis, as the drug is not effectively removed by hemodialysis.[12] This is a critical distinction from many other cardiovascular drugs and highlights the importance of understanding drug-specific clearance pathways.

Comparative Analysis and Clinical Context

To fully appreciate the role of metoprolol in clinical practice, it is useful to compare it to other beta-blockers and understand its position within current therapeutic guidelines.

Metoprolol vs. Other Beta-Blockers

Metoprolol belongs to a diverse class of drugs, and its properties differentiate it from other agents.

• Cardioselectivity: Metoprolol is a beta-1 selective antagonist, a property it shares with drugs like atenolol and bisoprolol. This selectivity makes it theoretically less likely to cause beta-2 mediated side effects, such as bronchospasm, compared to non-selective agents like propranolol or nadolol. However, this selectivity is relative and diminishes at higher doses.[12]
• Lipophilicity: Metoprolol is moderately lipophilic, which allows it to readily cross the blood-brain barrier.[4] This property is linked to its effectiveness in migraine prophylaxis but may also contribute to a higher incidence of central nervous system side effects (e.g., fatigue, sleep disturbances, depression) compared to more hydrophilic agents like atenolol, which do not penetrate the CNS as easily.
• Intrinsic Sympathomimetic Activity (ISA): Metoprolol lacks ISA, meaning it is a pure antagonist.[12] This contrasts with agents like pindolol or acebutolol, which have partial agonist activity and may cause less bradycardia at rest.
• Alpha-Adrenergic Blockade: Unlike carvedilol and labetalol, metoprolol possesses no alpha-blocking properties. The additional alpha-blockade of carvedilol and labetalol contributes to their vasodilatory effects and may provide different hemodynamic benefits.
• Clinical Efficacy: In comparative trials, metoprolol has been shown to be as effective as propranolol for the treatment of hypertension and angina.[3] Other studies have compared it to bisoprolol for hypertension management.[52]

Placement within Current Cardiovascular Treatment Guidelines

The role of beta-blockers in cardiovascular medicine has evolved over time. While they remain a vital drug class, their position as first-line therapy has been refined.

• Hypertension: For the initial management of uncomplicated hypertension, current guidelines from major societies often recommend ACE inhibitors, ARBs, or calcium channel blockers ahead of beta-blockers, particularly in certain patient populations.[37] Beta-blockers like metoprolol are considered a primary option when there is a compelling co-existing indication, such as ischemic heart disease or heart failure.
• Ischemic Heart Disease and Heart Failure: In contrast to hypertension, metoprolol (and other evidence-based beta-blockers) remains a first-line, cornerstone therapy for patients with stable angina, post-myocardial infarction, and chronic heart failure with reduced ejection fraction (HFrEF). In these conditions, its ability to reduce myocardial oxygen demand and protect the heart from chronic catecholamine toxicity provides a clear mortality and morbidity benefit.
• Arrhythmias: Metoprolol is a well-established agent for controlling the ventricular rate in patients with rapid atrial fibrillation and for managing other supraventricular tachycardias.

Conclusion and Future Perspectives

Metoprolol is a versatile and indispensable beta-1 selective adrenergic antagonist with a robust evidence base supporting its use across a spectrum of cardiovascular diseases. Its efficacy in hypertension, angina pectoris, acute myocardial infarction, and chronic heart failure has solidified its place in modern pharmacotherapy.

The clinical application of metoprolol is defined by a series of critical nuances. The most prominent of these is the distinction between its salt forms: the immediate-release tartrate and the extended-release succinate. This difference is not trivial, as it dictates dosing frequency, pharmacokinetic stability, and, most importantly, approved indications, with the succinate form holding a unique, evidence-based role in improving survival in heart failure. Safe and effective therapy requires a clear understanding that these formulations are not interchangeable.

Furthermore, the drug's heavy reliance on the polymorphic CYP2D6 enzyme for its metabolism is a key determinant of inter-individual variability in patient response and a major source of drug-drug interactions. This metabolic profile mandates a cautious approach to prescribing, characterized by slow dose titration and vigilance for both efficacy and adverse effects. The safety profile of metoprolol is a direct and predictable consequence of its pharmacology, with the boxed warning against abrupt cessation serving as a stark reminder of the physiological adaptations that occur during chronic therapy.

Looking forward, the primary avenue for advancing metoprolol therapy lies in the realm of personalized medicine. The well-defined role of CYP2D6 in its metabolism makes it a prime candidate for the application of pharmacogenetic testing. Pre-emptive genotyping could potentially allow clinicians to identify poor or ultra-rapid metabolizers before initiating therapy, enabling more precise, individualized dosing from the outset. This could optimize efficacy while minimizing the risk of adverse events, moving clinical practice from a reactive "trial-and-error" titration process to a more proactive, genetically-informed approach. Continued research into the long-term comparative effectiveness of metoprolol versus other beta-blockers in specific, well-defined patient subgroups could further refine treatment algorithms and ensure that this vital medication is used to its greatest potential.

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