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Saturday, August 16, 2025

Metoprolol


Executive overview

Metoprolol is a cardioselective β1-adrenergic receptor antagonist available as metoprolol tartrate (immediate-release, including IV) and metoprolol succinate (extended-release, once daily; also in sprinkle capsule form). Cardioselectivity is dose-dependent; at higher exposures, β2 effects can emerge. Its principal therapeutic effects are reduction in heart rate, myocardial contractility, and renin release, producing benefit across hypertension, chronic stable angina, post-myocardial infarction secondary prevention, rate control in supraventricular tachyarrhythmias, and—specifically for the succinate extended-release formulation—evidence-based disease-modifying therapy in stable HFrEF. Regulatory indications and labeling vary by country; the details below draw on major reference labels and summaries.

Pharmacologic class and formulations

  • Class: β-blocker, cardioselective (β1-preferential)

  • Salts/forms

    • Metoprolol tartrate (IR): oral tablets (commonly 50, 100 mg) and IV injection (1 mg/mL; 5 mg per 5 mL ampoule).

    • Metoprolol succinate (ER): once-daily extended-release tablets (25, 50, 100, 200 mg) and sprinkle capsules (some markets). ER tablets use a multiple-unit pellet system that releases drug over ~24 h. Strengths of 23.75, 47.5, 95, 190 mg succinate correspond to 25, 50, 100, 200 mg metoprolol tartrate equivalents.

  • Key equivalence rule: when converting IR tartrate to ER succinate for hypertension or angina, use the same total daily dose (adjust to clinical response).

  • Selectivity: β1-selective, without intrinsic sympathomimetic activity; membrane-stabilizing activity is negligible at usual doses.

Mechanism of action

Metoprolol competitively antagonizes β1 receptors in the sinoatrial node, AV node, and myocardium. This:

  1. slows the sinus rate and AV nodal conduction, 2) decreases myocardial contractility and oxygen demand, 3) suppresses renin secretion from juxtaglomerular cells. The combination reduces anginal symptoms and BP, and provides rate control in SVT/AF. In HFrEF, chronic β1 blockade counteracts deleterious sympathetic activation, improving outcomes when the ER succinate formulation is up-titrated to target doses alongside guideline-directed therapy.

Pharmacokinetics (clinically relevant points)

  • Absorption & bioavailability: rapid oral absorption; notable first-pass metabolism produces variable plasma levels.

  • Distribution: low protein binding (~12%); crosses the blood–brain barrier and placenta; appears in breast milk in small amounts.

  • Metabolism: hepatic, CYP2D6 predominates; phenotype and drug–drug interactions can raise levels several-fold.

  • Elimination half-life: ~3–7 h (IR), while ER provides flatter exposure over 24 h; <5% excreted unchanged in urine.

  • Special populations: renal impairment has limited effect on kinetics; hepatic impairment increases exposure—start low and titrate cautiously.

Evidence-based and common indications

Regulatory indications differ by region; confirm locally. Common, well-supported uses include:

  • Hypertension (monotherapy or add-on) – IR or ER

  • Chronic stable angina – IR or ER

  • Heart failure with reduced ejection fraction (HFrEF) – ER succinate is indicated and outcome-proven in stable, symptomatic patients when up-titrated to target dose

  • Rate control in supraventricular tachycardia and atrial fibrillation/flutter – IV for acute control (monitoring required), then oral maintenance

  • Post-myocardial infarction – early IV then oral IR; ongoing oral therapy for secondary prevention

  • Additional, commonly accepted off-label uses (jurisdiction-dependent): migraine prophylaxis, symptomatic control in thyrotoxicosis, hypertrophic obstructive cardiomyopathy symptoms, and prevention/treatment of tachyarrhythmias in various settings

Contraindications

  • Severe bradycardia

  • Second- or third-degree AV block, sick sinus syndrome (without pacemaker)

  • Cardiogenic shock or decompensated heart failure (until stabilized)

  • Severe hypotension

  • Hypersensitivity to metoprolol or formulation components

  • Untreated pheochromocytoma (require α-blockade first)

Warnings and precautions

  • Abrupt withdrawal risks ischemia, MI, and arrhythmia in coronary disease—taper over 1–2 weeks.

  • Heart failure: initiation/up-titration may transiently worsen symptoms; adjust diuretics and titrate slowly; defer dose increases until stable.

  • Bronchospastic disease: cardioselectivity is not absolute; avoid or use with great caution in active asthma/COPD with bronchospasm.

  • Diabetes: β-blockers may mask hypoglycemia-related tachycardia; reinforce glucose monitoring.

  • Peripheral vascular disease/Raynaud symptoms may worsen.

  • Anaphylaxis: treatment response to epinephrine can be blunted.

  • Major surgery: do not initiate high-dose ER peri-operatively; do not routinely stop chronic therapy—coordinate with anesthesia.

  • Hepatic impairment: start at lower doses; titrate more slowly.

  • Thyrotoxicosis: avoid abrupt cessation (risk of precipitating thyroid storm).

Adverse effects (clinically prominent)

  • Very common/common: fatigue, dizziness, bradycardia, hypotension, cold extremities, dyspnea, GI upset, pruritus/rash.

  • Neuropsychiatric (dose-related; more with lipophilic β-blockers): vivid dreams, insomnia, depressive symptoms, rarely hallucinations/confusion (elderly).

  • Cardiovascular: AV block, heart failure exacerbation if up-titrated too quickly, syncope.

  • Respiratory: bronchospasm in predisposed patients.

  • Other: sexual dysfunction, dry eyes, exacerbation of psoriasis.
    Most effects are dose-dependent and improve with dose reduction or formulation adjustment.

Clinically important drug interactions

  • CYP2D6 inhibitors can raise metoprolol exposure (and reduce cardioselectivity): paroxetine, fluoxetine, bupropion, quinidine, propafenone, ritonavir and some other protease inhibitors. Monitor HR/BP and reduce dose if needed.

  • Rate-slowing agents: verapamil, diltiazem, digoxin, amiodarone—additive bradycardia/AV block; avoid IV verapamil/diltiazem with IV β-blockers.

  • Clonidine: if both are used, taper β-blocker first before withdrawing clonidine to avoid rebound hypertension.

  • Catecholamine depletors (e.g., reserpine, MAO inhibitors): additive bradycardia/hypotension.

  • NSAIDs: may blunt antihypertensive effect.

  • Anaphylaxis treatment: higher or additional measures may be needed since β-blockers can attenuate epinephrine efficacy.

Dosing and administration by indication

General principles

  • Titrate to clinical endpoints (symptom relief, HR, BP), not a fixed number.

  • For ER succinate, administer once daily; tablets may be split along the score but do not crush or chew pellets.

  • For IR tartrate, give with or immediately after meals; typically twice daily.

  • When converting IR → ER, use the same total daily dose, then adjust.

  • Do not exceed 400 mg/day for hypertension/angina regimens studied in adults.

Hypertension — adults

  • IR (metoprolol tartrate): initial 100 mg/day in single or divided doses; usual maintenance 100–450 mg/day in 2–3 doses.

  • ER (metoprolol succinate): initial 25–100 mg once daily; titrate every ≥1 week to effect; dosages >400 mg/day have not been studied for hypertension.

  • Elderly: begin at the lower end of the range and up-titrate more slowly.

  • Renal impairment: generally no adjustment.

  • Hepatic impairment: consider lower starting dose and careful titration.

Hypertension — pediatrics (≥6 years; ER only)

  • If selected for treatment: 1.0 mg/kg once daily, max initial 50 mg; adjust to BP response. Doses >2 mg/kg or >200 mg/day not studied. Not recommended <6 years.

Chronic stable angina

  • IR: usual initial 100 mg/day divided; titrate weekly to 100–400 mg/day divided.

  • ER: usual initial 100 mg once daily; titrate weekly to response (up to 400 mg/day). Dose-limiting bradycardia often determines ceiling.

Heart failure with reduced ejection fraction (stable, symptomatic) — ER only

  • Ensure the patient is euvolemic and background ACEi/ARB/ARNI + diuretic (± MRA, SGLT2i) are stabilized before initiation.

  • Starting dose:

    • NYHA II: 25 mg once daily for 2 weeks

    • NYHA III–IV or more symptomatic: 12.5 mg once daily for 2 weeks

  • Up-titration: double the dose every 2 weeks as tolerated to the highest tolerated dose or 200 mg once daily.

  • Temporarily down-titrate or hold if bradycardia, hypotension, or HF decompensation develops; re-attempt titration once stable.

Post-myocardial infarction (secondary prevention; IR regimen)

  • Early in-hospital phase (hemodynamically stable): 5 mg IV over 1–2 min every ~2 min ×3 (total 15 mg), with continuous ECG and BP monitoring.

  • Follow with oral IR: 50 mg every 6 h for 48 h, then 100 mg twice daily.

  • If IV not tolerated, begin oral IR 25–50 mg every 6 h as soon as feasible, then aim for 100 mg twice daily. Continue for at least several months per local guidance.

Supraventricular tachyarrhythmias and AF rate control

  • IV acute control (IR): 2.5–5 mg IV over several minutes, repeat q2–5 min to a max 15 mg, with ECG/BP monitoring (avoid in decompensated HF or severe bronchospasm).

  • Oral maintenance: IR 25–100 mg twice daily or ER equivalent total daily dose once daily, titrated to achieve rate goals at rest and with light activity.

Migraine prophylaxis (off-label; jurisdiction-specific)

  • Evidence supports β-blockers as first-line preventives in episodic migraine. For metoprolol, typical effective totals are 100–200 mg/day (e.g., IR 50–100 mg twice daily or ER 100–200 mg once daily).

  • Start lower (e.g., 25–50 mg/day), increase every 2–4 weeks; assess efficacy after 2–3 months of a stable dose.

Symptomatic thyrotoxicosis (off-label)

  • β-blockade mitigates adrenergic symptoms (tremor, palpitations, anxiety) while disease-specific therapy is instituted. Typical practice: IR 25–50 mg twice daily, titrated to symptom control and heart rate; higher doses may be required in severe thyrotoxicosis. Avoid abrupt withdrawal.

Practical switching and titration notes

  • IR → ER: consolidate to once-daily ER at the same total daily milligram amount, then adjust. Many patients need less peak-to-trough variability; ER’s multi-unit pellets smooth exposure.

  • ER tablet handling: tablets are scored and can be split; do not crush/chew pellets.

  • Up-titration intervals: hypertension/angina typically ≥1 week; heart failure every 2 weeks as tolerated.

Monitoring

  • Heart rate and BP at baseline and after dose changes; review for symptomatic bradycardia, dizziness, syncope.

  • ECG if conduction disease suspected or when combining with other rate-slowing drugs.

  • Volume status and HF symptoms during HF titration; adjust diuretics proactively.

  • Glycemic control in diabetes; educate about masked adrenergic symptoms of hypoglycemia.

  • Drug interaction review at initiation and when antidepressants/antiarrhythmics/antiretrovirals are added.

  • Pregnancy and lactation: see below.

Pregnancy and lactation

  • Pregnancy: use only if clearly needed after risk–benefit assessment. β-blockers have been associated with fetal growth restriction in some contexts; if continued, obstetric teams commonly add fetal growth surveillance in the third trimester per local practice.

  • Breastfeeding: metoprolol appears in milk in small amounts; multiple authoritative sources consider it compatible with breastfeeding in healthy term infants, with routine observation for infant bradycardia, poor feeding, or unusual sleepiness.

Patient counseling points

  • Take metoprolol consistently with food (especially IR) to stabilize absorption.

  • Do not stop suddenly; doses are tapered to avoid rebound ischemia or tachyarrhythmia.

  • Report new/worsening shortness of breath, fainting, very slow pulse, cold/painful extremities, or mood changes.

  • In diabetes, monitor glucose more closely and learn non-tachycardic signs of hypoglycemia (sweating, confusion).

  • Avoid over-the-counter NSAIDs that may blunt BP control unless advised.

  • If using inhaled β-agonists for bronchospasm, let your prescriber know; dose adjustments may be needed.

  • For ER tablets, do not crush or chew; for IV therapy, continuous monitoring is required.



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