Metoprolol Tartrate

Introduction Overview

Generic Name

metoprolol tartrate

Brand Name

Lopressor

Dosage Form

tablet

Drug Class

Cardioselective beta blockers

Pharmacokinetics

Metoprolol tartrate exhibits complex pharmacokinetic characteristics that are critically important for its clinical use and dose optimization.

Absorption:
Metoprolol tartrate is administered orally, with an estimated bioavailability of about 50%. This reduced bioavailability is primarily due to first-pass hepatic metabolism, which is saturable and causes non-proportional increases in plasma concentration with increasing dose. Peak plasma levels are typically reached within 1 to 2 hours post-ingestion. The absorption is not significantly affected by food, but the medication is recommended to be taken with or immediately after meals to ensure consistent absorption and to minimize gastrointestinal side effects.

Distribution:
This drug has a large volume of distribution ranging from approximately 3.2 to 5.6 L/kg, indicating extensive tissue uptake. Metoprolol is approximately 10% bound to plasma proteins, specifically serum albumin. It readily crosses physiological barriers, including the placenta and blood-brain barrier, achieving cerebrospinal fluid concentrations close to plasma levels, which may contribute to some central nervous system-related side effects. It is also excreted in breast milk, necessitating monitoring for neonatal effects in breastfeeding mothers.

Metabolism:
Metoprolol is extensively metabolized primarily by the cytochrome P450 2D6 (CYP2D6) enzyme in the liver. It is a racemic mixture of R- and S-enantiomers, with stereoselective metabolism that is dependent on individual CYP2D6 genotype. Approximately 8% of Caucasians and 2% of other ethnic groups are poor metabolizers due to absent or deficient CYP2D6 activity, resulting in markedly higher plasma concentrations and prolonged half-life of metoprolol. The metabolism variability affects both efficacy and safety and decreases the drug's beta1-selectivity at higher plasma levels.

Elimination:
The elimination half-life of metoprolol is generally 3 to 4 hours in extensive metabolizers, but in poor metabolizers, it can extend from 7 to 9 hours. Approximately 95% of the drug dose is recovered in urine, predominantly as metabolites, with less than 5-10% excreted unchanged in extensive metabolizers; poor metabolizers may excrete up to 30-40% unchanged drug. Renal clearance does not display stereoselectivity. Hepatic impairment can significantly increase systemic exposure, warranting dose adjustments. Renal impairment does not significantly alter pharmacokinetics. Overall, metoprolol's pharmacokinetics necessitate individualized dosing and careful consideration of CYP2D6 status and hepatic function.

Dosage Forms

Available Dosage Forms:
Lopressor is supplied exclusively as an immediate-release oral tablet.
- 50 mg tablet — capsule-shaped, biconvex, pink, scored, imprinted "LOPRESSOR" and "458" twice on the scored side.
- 100 mg tablet — capsule-shaped, biconvex, light blue, scored, imprinted "LOPRESSOR" and "459" twice on the scored side.

Dosages for Adults and Adolescents:
- Hypertension: The usual initial dose is 100 mg daily, administered as once daily or divided doses. Dosages are titrated at weekly or longer intervals from 100 mg up to 450 mg per day depending on clinical response. Doses above 450 mg daily have not been studied.
- Angina Pectoris: Initial dose typically 100 mg daily in two divided doses, gradually increased up to 400 mg daily based on clinical efficacy and heart rate response.
- Myocardial Infarction (hemodynamically stable patients): Following intravenous metoprolol treatment, initiate with 50 mg orally every 6 hours for 48 hours; if intolerance occurs, reduce to 25 mg every 6 hours. Maintenance dosing is typically 100 mg twice daily continued for at least 3 months.

Specific Patient Populations:
- Geriatric: Begin with lower doses due to decreased hepatic metabolism and comorbidities; monitor closely.
- Hepatic impairment: Initiate at lower doses with gradual titration due to reduced metabolism and increased plasma levels.
- Renal impairment: No dosage adjustment generally required.
- Pediatric: Safety and efficacy not established; use not recommended.

Clinical Guidelines:
Lopressor should be taken with or immediately following meals to ensure optimal absorption. When discontinuing therapy, gradual tapering over 1 to 2 weeks is necessary to avoid exacerbations of angina or myocardial ischemia. Dose should be individualized based on patient tolerance, clinical response, and hemodynamics monitored regularly.

Mechanism Of Action

Metoprolol tartrate, the active ingredient in Lopressor, is a beta1-selective adrenergic receptor antagonist that primarily targets beta1-adrenergic receptors located in cardiac tissue. By competitively inhibiting the binding of endogenous catecholamines such as norepinephrine and epinephrine to these receptors, metoprolol suppresses sympathetic stimulation of the heart. This results in decreased heart rate (negative chronotropy), reduced myocardial contractility (negative inotropy), and slowed atrioventricular conduction (negative dromotropy), thereby diminishing myocardial oxygen demand.

The cardioselectivity of metoprolol arises from its preferential blockade of beta1 receptors over beta2 receptors, the latter being predominant in bronchial and vascular smooth muscle. While selectivity is maintained at therapeutic plasma concentrations, at higher concentrations this selectivity diminishes, potentially leading to beta2 antagonism and associated bronchospasm. Metoprolol lacks intrinsic sympathomimetic activity and membrane-stabilizing effects, ensuring that its beta-blocking action is not confounded by partial agonist effects or sodium channel blockade.

In hypertension, metoprolol's antihypertensive mechanism is multi-factorial: it competitively antagonizes peripheral beta1-adrenergic receptors, reducing cardiac output by decreasing heart rate and contractility; it suppresses central sympathetic outflow, leading to decreased peripheral vascular resistance; and it diminishes renin release from juxtaglomerular cells, reducing angiotensin II-mediated vasoconstriction and aldosterone secretion. These combined effects contribute to blood pressure reduction.

In angina pectoris, metoprolol's heart rate and contractility reduction limits catecholamine-stimulated increases in myocardial oxygen demand, improving the oxygen supply-demand balance. This mechanism effectively reduces the frequency and severity of anginal attacks and improves exercise tolerance.

The beneficial effects in myocardial infarction include reduction in infarct size and mortality, by limiting excessive sympathetic stimulation, reducing myocardial workload and oxygen consumption, stabilizing cardiac electrical activity, and preventing arrhythmias. Intravenous administration immediately post-infarct provides rapid beta1 blockade, followed by sustained oral therapy for ongoing protection.

Overall, metoprolol's selective blockade of beta1-adrenergic receptors translates clinically into effective control of hypertension, angina, and improved survival post-myocardial infarction while minimizing adverse pulmonary effects relative to nonselective beta-blockers.

Pharmacological Actions

Selective beta1-adrenergic receptor blockade resulting in decreased heart rate, myocardial contractility, and conduction velocity.
Reduction of myocardial oxygen demand through negative chronotropic and inotropic effects.
Suppression of renin release from renal juxtaglomerular cells, leading to decreased angiotensin II formation and aldosterone secretion.
Central sympatholytic effects reducing peripheral sympathetic outflow and vascular resistance.
Management of hypertension through combined cardiac and renal beta1 blockade.
Antianginal effects by limiting ischemic myocardial workload.
Antiarrhythmic properties by slowing AV nodal conduction and reducing automaticity.
Reduction in mortality and morbidity post-acute myocardial infarction by limiting cardiac workload and preventing arrhythmias.
Minimal intrinsic sympathomimetic activity, ensuring pure antagonistic beta-blocking effects.
Absence of significant membrane-stabilizing activity at therapeutic concentrations.

Therapeutic Or Clinical Uses

Management of essential hypertension to reduce blood pressure and decrease cardiovascular risk.
Long-term treatment of angina pectoris to reduce frequency of anginal attacks and improve exercise tolerance.
Reduction of cardiovascular mortality in hemodynamically stable patients following acute myocardial infarction, in conjunction with intravenous metoprolol therapy.
Use in combination with other antihypertensive agents for enhanced blood pressure control.
Off-label use may include treatment of certain cardiac arrhythmias due to AV nodal conduction slowing.
Management of stable ischemic heart disease patients who require heart rate control.
Secondary prevention following myocardial infarction to reduce recurrent cardiac events.
Part of comprehensive cardiovascular risk-management strategies, including lipid and diabetes control.

Side Or Adverse Effects

Fatigue and tiredness reported in approximately 10% of patients.
Dizziness, which may contribute to fall risk in elderly patients.
Depression, reported in about 5% of treated patients.
Short-term memory loss and occasional mental confusion.
Headache, nightmares, and insomnia as central nervous system effects.
Bradycardia occurring in about 3% of patients; may necessitate dose adjustment.
Hypotension, including symptomatic cases, especially in early therapy or dose titration.
Cold extremities and Raynaud's phenomenon due to peripheral vasoconstriction.
Worsening or new onset of heart failure in predisposed individuals during up-titration.
Bronchospasm and wheezing, particularly in patients with reactive airway diseases.
Gastrointestinal disturbances including diarrhea, nausea, dry mouth, gastric pain, constipation, flatulence, and vomiting.
Hypersensitivity reactions, such as pruritus, rash, photosensitivity, and exacerbation of psoriasis.
Peripheral edema and palpitations.
Rare reports of Peyronie’s disease and musculoskeletal pain.
Post-marketing reports include agranulocytosis, thrombocytopenic purpura, and reversible mental depression progressing to catatonia.

Precautions

Avoid abrupt cessation of therapy to prevent exacerbations of angina, myocardial infarction, or rebound hypertension; taper dosage gradually over 1 to 2 weeks.
Use cautiously in patients with a history of heart failure; monitor for signs of worsening cardiac function during dose titration.
Exercise caution in patients with bronchospastic disease; use lowest effective doses and ensure availability of bronchodilators.
In patients with pheochromocytoma, initiate beta-blockade only after alpha blockade is established to prevent hypertensive crises.
Monitor diabetic patients carefully as beta-blockers may mask signs and symptoms of hypoglycemia and prolong hypoglycemic episodes.
Avoid initiation of high-dose beta-blockade in patients undergoing non-cardiac surgery due to risk of bradycardia, hypotension, stroke, and death.
In patients undergoing major surgery, continuation but not withdrawal of chronic beta-blocker therapy is generally recommended.
Be alert for potential rebound tachycardia and hypertension upon withdrawal, especially in patients previously treated with clonidine.
In patients with peripheral vascular disease, beta-blockers may aggravate arterial insufficiency; monitor for worsening symptoms.
Close monitoring required in patients with hepatic impairment due to risk of increased drug plasma levels.
Monitor elderly patients closely due to possible decreased hepatic metabolism and increased susceptibility to side effects.
Advise patients about potential for fatigue and dizziness and precautions against activities requiring alertness until stabilized.
Assess bradycardia risk, especially in combination with other negative chronotropes like digitalis or calcium channel blockers.
Inform patients regarding the risk of hypoglycemia masking and anaphylactic reaction susceptibility.
Encourage adherence and consultation before dose adjustment or discontinuation.

Warnings

Abrupt discontinuation may precipitate acute myocardial ischemia, angina, or myocardial infarction.
Worsening of heart failure may occur; titrate doses carefully and adjust concomitant heart failure therapy.
Use with caution in patients with bronchospastic diseases; potential for bronchospasm remains due to non-absolute beta1 selectivity.
When used in pheochromocytoma without alpha blockade, may cause paradoxical hypertension.
Initiation of beta-blockers at high doses in non-cardiac surgery patients is associated with increased risk of bradycardia, hypotension, stroke, and death.
Diabetes patients may experience masking of hypoglycemia symptoms and prolonged hypoglycemia episodes.
Sudden withdrawal can exacerbate thyrotoxicosis or precipitate thyroid storm.
Patients with prior severe anaphylactic reactions may display increased reactivity and reduced responsiveness to epinephrine when on beta-blockers.
May aggravate peripheral vascular insufficiency symptoms and precipitate gangrene in severe cases.
Contraindicated in severe bradycardia, advanced AV block, cardiogenic shock, decompensated heart failure, and sick sinus syndrome without a pacemaker.

Contraindication

Known hypersensitivity to metoprolol or any component of the formulation.
Severe bradycardia, including greater than first-degree heart block, and sick sinus syndrome without pacemaker.
Cardiogenic shock and decompensated heart failure.
Second- or third-degree atrioventricular block.
Systolic blood pressure less than 100 mm Hg at treatment initiation.
Patients with severe peripheral arterial circulatory disorders.
Use in combination with intravenous metoprolol is contraindicated in hemodynamically unstable acute myocardial infarction patients.

Drug Interactions

Catecholamine-depleting agents (e.g., reserpine, monoamine oxidase inhibitors) may have additive hypotensive and bradycardic effects when combined with Lopressor.
Concomitant use with CYP2D6 inhibitors such as quinidine, fluoxetine, paroxetine, and propafenone can significantly increase plasma concentrations of metoprolol, reducing cardioselectivity and increasing risk of adverse effects.
Concurrent administration with digitalis glycosides, clonidine, diltiazem, and verapamil can lead to additive negative chronotropic effects, increasing risk of bradycardia and conduction block.
Co-administration with clonidine requires gradual withdrawal of beta-blocker before clonidine to prevent rebound hypertension.
Lopressor may attenuate the usual therapeutic response to epinephrine used during anaphylactic reactions.
Beta-blockers may exacerbate rebound hypertension following clonidine withdrawal if not managed carefully.
Potential interaction with other antihypertensive agents leading to enhanced blood pressure lowering and risk of hypotension.
Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce antihypertensive efficacy of beta-blockers.
Concurrent use of insulin or oral hypoglycemic agents may mask signs of hypoglycemia and potentiate hypoglycemic episodes.
Drugs affecting hepatic enzyme systems may alter metoprolol metabolism and plasma levels, requiring dose adjustments.
Use caution when combining with other central nervous system agents due to potential additive CNS depressant effects.
Concomitant use with ergot alkaloids may increase risk of vasospastic responses.

Preparations Of The Drug

Lopressor is available as oral immediate-release tablets in two strengths: 50 mg (pink, capsule-shaped, biconvex, scored tablets) and 100 mg (light blue, capsule-shaped, biconvex, scored tablets).
Tablets contain inactive ingredients including microcrystalline cellulose, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, povidone, sodium starch glycolate, polyethylene glycol, propylene glycol, talc, and titanium dioxide.
Film coatings differ by strength: Opadry YS-1-1419 Pink for the 50 mg tablets, and Opadry YS-1-4281 Blue for the 100 mg tablets.
Distributed in bottles containing 100 tablets, with NDC codes 30698-458-01 (50 mg) and 30698-459-01 (100 mg).
Stored at controlled room temperature (59° to 86°F or 15° to 30°C), protected from moisture and heat in tight, light-resistant containers.