Metoprolol

Mechanism

Mechanism of Action

Highly selective competitive antagonist of cardiac β₁ adrenergic receptors, with minimal affinity for β₂ receptors in bronchial and vascular smooth muscle at usual therapeutic concentrations. It lacks intrinsic sympathomimetic activity and shows little clinically relevant membrane stabilizing activity. It selectively decreases heart rate, stroke volume, cardiac output and myocardial perfusion pressure at rest and during physical effort, significantly reducing nodal conduction velocity and preventing tachycardia induced by adrenergic effort.

Pharmacokinetics

Key Pharmacokinetics

Metoprolol is prescribed commercially in two formulations with markedly different biopharmaceutical profiles:

Metoprolol Tartrate

• Effect: Short-acting immediate release formulation.
• Preferred indication: Hypertension, angina, acute infarction in the hyperacute phase.
• Dosage frequency: Requires taking doses every 12 hours or less.
• Absorption: Rapid, with a plasma peak at 1.5-2 hours.

Metoprolol Succinate

• Effect: Flat profile extended release formulation.
• Preferred indication: Compensated chronic systolic heart failure.
• Dosage frequency: A single dose every 24 hours.
• Serum stability: Avoids undesirable high blood pressure and bradycardia peaks from fractional intakes.

Indicators and dose

Approved and Off-label Indications

Approved: Essential arterial hypertension; chronic stable angina pectoris; moderate to severe stable chronic congestive heart failure with reduced ejection fraction (extended-release metoprolol succinate formulation only); prophylaxis of acute myocardial infarction in the acute phase and post-infarction intervention.

Off-label: Rhythm control in atrial fibrillation with rapid ventricular response; prophylaxis of refractory migraine.

Dosage and Adjustments

Systolic Heart Failure (Succinate): Start with 12.5-25 mg orally once a day. Double the dose every 2 weeks as tolerated by the patient until reaching an optimal target dose of 200 mg/day continuously.

Hypertension (Tartrate): 50-100 mg/day divided into one or two doses.

Renal adjustment: Does not require modifications to the ordinary dosimetric regimen.

Hepatic adjustment: It undergoes extensive hepatic metabolism. In the case of advanced cirrhosis or Child-Pugh class B/C, a reduction in the starting dose by 50% and increases more spaced over time is recommended.

Security

Contraindications

Absolute: Severe sinus bradycardia, second or third degree AV block without pacemaker device, cardiogenic shock, active acute decompensated heart failure (patients admitted to the ICU with positive IV inotropic therapy).

Relative: Active bronchial asthma that is difficult to control, history of reactive airway disease at maximum doses of the drug (loss of β₁ cardiac selectivity).

Adverse Effects (ADR)

Frequent: Orthostatic dizziness, asthenia, moderate bradycardia, symptomatic arterial hypotension at the beginning of therapy, mild dyspnea on exertion, distal coldness of extremities.

Serious: Advanced heart block, acute bronchospasm (in high doses where pharmacological selectivity is lost), severe exacerbation of chronic heart failure if the introduction of the drug is not carried out slowly and progressively.

Interactions

Potent CYP2D6 inhibitors (e.g., paroxetine, bupropion, fluoxetine): They double or triple the serum concentrations of metoprolol, favoring the loss of selectivity and potentiating bradycardic adverse effects.

Negative dromotropic agents (verapamil, amiodarone): Extreme depressant synergy of the atrioventricular conduction node.

Pregnancy and Breastfeeding

FDA Classification: Category C. May induce fetal bradycardia, transient hypotension and immediate neonatal hypoglycemia. Metoprolol is excreted in clinically insignificant quantities in breast milk, allowing its use under pediatric supervision of the infant.