What does metoprolol do?

What Metoprolol Does

Metoprolol is a beta-1 selective (cardioselective) adrenergic receptor blocker that reduces heart rate, cardiac output, blood pressure, and myocardial oxygen demand, making it effective for treating hypertension, angina, heart failure, and acute myocardial infarction. 1

Mechanism of Action

Metoprolol works by preferentially blocking beta-1 adrenergic receptors in the heart, though this selectivity is not absolute at higher doses, where it also inhibits beta-2 receptors in bronchial and vascular smooth muscle. 1 The drug demonstrates its beta-blocking activity through four key effects:

• Reduces heart rate and cardiac output both at rest and during exercise 1
• Lowers systolic blood pressure during physical exertion 1
• Inhibits isoproterenol-induced tachycardia (blocks catecholamine effects) 1
• Reduces reflex orthostatic tachycardia 1

Cardiovascular Effects by Condition

In Hypertension: The antihypertensive mechanism involves competitive antagonism of catecholamines at cardiac adrenergic receptors (decreasing cardiac output), central effects reducing sympathetic outflow, and suppression of renin activity. 1 Metoprolol produces modest blood pressure reductions averaging 4 mmHg systolic and 3 mmHg diastolic at recommended doses. 2

In Angina Pectoris: Metoprolol blocks catecholamine-induced increases in heart rate, myocardial contractility velocity/extent, and blood pressure, thereby reducing myocardial oxygen requirements at any given workload. 1 It prolongs diastole, improving perfusion of ischemic myocardial areas, and may counteract coronary vasospasm through reduction of sympathetic tone. 3

In Heart Failure: Metoprolol antagonizes the deleterious effects of chronic sympathetic nervous system activation. 4 Long-term norepinephrine exposure causes myocardial toxicity, fibrosis, necrosis, progressive ventricular remodeling, beta-1 receptor downregulation, and apoptosis—all of which metoprolol interrupts through beta-1 blockade. 3 Beta-blockade reverses left ventricular remodeling by decreasing myocardial mass and LV volume, leading to improved ejection fraction and cardiac index over time. 4, 3

In Acute Myocardial Infarction: When administered intravenously followed by oral therapy, metoprolol causes reductions in heart rate, systolic blood pressure, and cardiac output while maintaining stroke volume and diastolic pressure. 1 In the METOCARD-CNIC trial, intravenous metoprolol (35 mg) given prior to primary PCI reduced infarct size, prevented LV adverse remodeling, preserved LV function, and lowered heart failure hospitalizations. 4

Clinical Efficacy Data

Heart Failure Outcomes

Metoprolol succinate (controlled-release) reduced all-cause mortality by 34% in the MERIT-HF trial of 3,991 patients with NYHA class II-IV heart failure. 4 The drug also achieved:

• 38% reduction in cardiovascular mortality 4
• 41% reduction in sudden death 4
• 49% reduction in death from progressive heart failure 4
• 35% reduction in heart failure hospitalizations 4

Treating 27 patients with metoprolol for one year prevents one death. 4

Formulation-Specific Considerations

Critical distinction: Metoprolol succinate (sustained-release) is the formulation proven to reduce mortality in heart failure, whereas metoprolol tartrate (immediate-release) lacks proven mortality benefits and performed worse than carvedilol in the COMET trial. 5, 2 For heart failure patients, metoprolol succinate is mandatory—start at 12.5-25 mg once daily and titrate to target dose of 200 mg once daily. 5

For hypertension alone, either formulation is acceptable, though succinate is preferred for once-daily convenience and consistent 24-hour coverage. 5

Pharmacokinetics and Important Caveats

Oral bioavailability is approximately 50% due to saturable pre-systemic metabolism, leading to non-proportionate increases in exposure with higher doses. 1 Metoprolol is primarily metabolized by CYP2D6, and poor metabolizers (about 8% of Caucasians) exhibit several-fold higher plasma concentrations, decreasing cardioselectivity and increasing adverse effects. 1

Women achieve 50-100% higher plasma exposure due to slower CYP2D6 metabolism, often requiring lower doses to avoid excessive heart rate and blood pressure reductions. 2

Contraindications and Precautions

Avoid metoprolol in patients with:

• Severe heart failure or cardiogenic shock (especially IV administration) 4
• Evidence of low output state 4
• PR interval >0.24 seconds, second- or third-degree heart block 4
• Active asthma or reactive airway disease 4
• Systolic BP <120 mmHg, especially if age >70 years 4

The COMMIT/CCS-2 trial demonstrated that early IV metoprolol in acute MI caused 11 excess cardiogenic shock cases per 1,000 patients treated, particularly in high-risk patients (elderly, hypotensive, tachycardic, or Killip class >1). 4 Therefore, IV metoprolol should only be given to hemodynamically stable STEMI patients, preferably those with hypertension and no increased cardiogenic shock risk. 4

Hemodynamic Profile

Metoprolol slows sinus rate and decreases AV nodal conduction. 1 Maximum beta-blockade is achieved approximately 20 minutes after IV infusion, with oral-to-IV dose equivalence of approximately 2.5:1. 1 The drug crosses the placenta, appears in breast milk, and crosses the blood-brain barrier with CSF concentrations approaching plasma levels. 1

Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing effects only occur at doses far exceeding those needed for beta-blockade. 1