Metoprolol

1. Drug Name

• Generic Name: Metoprolol

• Brand Names: Lopressor, Toprol XL, Betaloc, Metolar, and others.

2. Drug Classification

• Class: Beta-blocker (Selective Beta-1 Adrenergic Antagonist)

• Subclass: Beta-1 Selective Blocker

3. Mechanism of Action

Metoprolol is a selective beta-1 adrenergic antagonist, commonly known as a beta-blocker. It works by blocking the beta-1 receptors in the heart, which results in:

• Decreased Heart Rate: By inhibiting beta-1 receptors, metoprolol reduces the effect of sympathetic nervous stimulation, leading to a slower heart rate (negative chronotropy).

• Reduced Contractility: Metoprolol decreases myocardial contractility (negative inotropy), lowering the heart's oxygen demand.

• Decreased Blood Pressure: It also lowers blood pressure by reducing cardiac output, which is directly related to heart rate and stroke volume.

• Antiarrhythmic Effects: By slowing the electrical conduction through the heart, metoprolol can help stabilize abnormal heart rhythms (arrhythmias).

• Angina Prevention: By reducing myocardial oxygen demand, it helps prevent chest pain (angina) due to ischemia.

Metoprolol’s selectivity for beta-1 receptors makes it more heart-specific, meaning it is less likely to cause bronchoconstriction or interfere with peripheral vascular tone, which are common side effects of non-selective beta-blockers.

4. Pharmacokinetics

• Absorption: Metoprolol is well absorbed after oral administration, with bioavailability varying between 40% to 50%, due to extensive first-pass metabolism in the liver.

• Distribution: The volume of distribution (Vd) is approximately 2-5 L/kg. Metoprolol is about 12% to 15% protein-bound in the plasma and is widely distributed throughout the body, including the brain.

• Metabolism: Metoprolol is primarily metabolized in the liver by cytochrome P450 enzymes, particularly CYP2D6. Genetic variations in CYP2D6 can influence the metabolism of metoprolol, leading to different therapeutic responses.

• Excretion: The half-life (t½) of metoprolol is approximately 3-7 hours for the immediate-release formulation and 10-12 hours for the extended-release formulation. Metoprolol is mainly excreted in the urine, with a significant portion as metabolites.

• Special Considerations: Metoprolol should be used cautiously in patients with hepatic impairment due to its hepatic metabolism. In renal impairment, dose adjustments may be required based on the clinical condition.

5. Indications

• Primary Indications:

  • Hypertension: Metoprolol is used to treat high blood pressure, either alone or in combination with other antihypertensive agents.

  • Angina Pectoris: It helps in preventing chest pain due to coronary artery disease by reducing myocardial oxygen demand.

  • Heart Failure (HF): In stable heart failure, metoprolol reduces mortality and morbidity.

  • Post-Myocardial Infarction: It is used to reduce the risk of reinfarction and sudden cardiac death after an MI.

  • Arrhythmias: Metoprolol is effective in controlling certain types of arrhythmias, such as atrial fibrillation or ventricular tachycardia.

• Off-Label Uses:

  • Migraine Prophylaxis: It may be used off-label to prevent migraine headaches.

  • Hyperthyroidism: It is used to manage symptoms such as tachycardia and palpitations associated with hyperthyroidism.

  • Performance Anxiety: Occasionally used to reduce symptoms like tremors and anxiety during high-stress situations.

  • Panic Attacks: It may help manage symptoms of anxiety disorders, particularly those involving physical symptoms like palpitations.

6. Dosage and Administration

• Adult Dosing:

  • Hypertension:

    • Immediate-Release: Start at 50 mg orally once daily, titrated up to a maximum dose of 100-200 mg per day.

    • Extended-Release: Start at 25-50 mg once daily, titrated up to 100-200 mg per day.

  • Angina:

    • 50 mg orally twice daily, with a possible increase to 100-200 mg daily depending on the patient's response.

  • Heart Failure:

    • Start with 12.5–25 mg once daily, gradually increasing to a target dose of 200 mg daily based on tolerance.

  • Post-Myocardial Infarction:

    • Start within 24 hours after an MI with 25 mg twice daily, titrated to 100-200 mg per day.

• Pediatric Dosing:

  • Typically used in children ≥6 years for hypertension. Dosing is based on weight, typically 0.5–1 mg/kg/day, divided into two doses.

• Renal Impairment: Adjustments may be necessary for severe renal impairment, although no specific dose recommendations are provided. Monitoring of renal function is essential.

• Maximum Safe Dose: The usual maximum dose is 200 mg/day for hypertension and 400 mg/day for angina.

7. Contraindications

• Absolute Contraindications:

  • Severe Bradycardia (heart rate <45 bpm)

  • 2nd or 3rd Degree AV Block: Metoprolol can worsen heart block and cause further conduction issues.

  • Severe Hypotension (systolic BP <90 mmHg)

  • Severe Heart Failure (decompensated)

  • Hypersensitivity to metoprolol or other beta-blockers

• Relative Contraindications:

  • Asthma and COPD: Caution is needed as beta-blockers, even selective ones, can cause bronchospasm in some patients.

  • Peripheral Vascular Disease: May exacerbate symptoms by further reducing peripheral blood flow.

  • Diabetes: May mask hypoglycemic symptoms like tachycardia.

8. Warnings and Precautions

• Black Box Warnings:

  • Abrupt Discontinuation: Sudden withdrawal of metoprolol can lead to a rebound increase in heart rate and blood pressure, potentially precipitating a myocardial infarction or arrhythmia. Gradual tapering over 1-2 weeks is recommended.

• Special Warnings:

  • Bradycardia and Heart Block: Monitor for slow heart rates, especially in patients with a history of conduction disorders.

  • Hypoglycemia: Metoprolol may mask the signs and symptoms of hypoglycemia (tachycardia), particularly in diabetic patients.

  • Heart Failure: Metoprolol should only be started in stable heart failure patients as it may exacerbate symptoms in acute decompensated heart failure.

  • Liver Disease: Use with caution in hepatic impairment.

• Monitoring Parameters:

  • Regular monitoring of heart rate and blood pressure.

  • ECG for patients with conduction disorders.

  • Blood glucose levels for diabetic patients.

9. Adverse Effects

• Common Adverse Effects:

  • Fatigue

  • Dizziness

  • Bradycardia (slow heart rate)

  • Hypotension

  • Depression

• Less Common but Clinically Significant Side Effects:

  • Bronchospasm (especially in patients with asthma or COPD)

  • Heart block or conduction disturbances

  • Cold extremities due to reduced peripheral circulation

• Rare/Serious Adverse Reactions:

  • Severe hypotension or shock

  • Heart failure exacerbation

  • Severe bradycardia (<40 bpm)

  • Liver enzyme elevation (hepatotoxicity)

  • Raynaud’s phenomenon or peripheral vascular disease

10. Drug Interactions

• Major Drug Interactions:

  • Calcium Channel Blockers (e.g., verapamil, diltiazem): Combined use can lead to excessive bradycardia, heart block, and hypotension.

  • Antiarrhythmics (e.g., amiodarone): Risk of bradycardia and heart block.

  • Clonidine: If clonidine is discontinued abruptly while on metoprolol, there is a risk of severe rebound hypertension.

  • NSAIDs: May reduce the antihypertensive effects of metoprolol.

  • Insulin and Oral Hypoglycemic Agents: Can mask symptoms of hypoglycemia and increase the risk of severe hypoglycemia.

• Food-Drug Interactions:

  • Food does not significantly affect the bioavailability of metoprolol. However, it is generally recommended to take metoprolol with food to reduce the risk of gastrointestinal upset.

11. Clinical Pharmacology

Metoprolol is a cardioselective beta-1 receptor antagonist. By blocking these receptors, it decreases heart rate, myocardial contractility, and systemic vascular resistance, thereby lowering blood pressure and reducing myocardial oxygen demand. It is commonly used in the management of hypertension, ischemic heart disease, heart failure, and arrhythmias.

12. Special Populations

• Pregnancy: Metoprolol is classified as Pregnancy Category C. It should be used only if the potential benefit justifies the potential risk to the fetus.

• Lactation: Metoprolol is excreted in breast milk, and although it is considered safe, it should be used with caution in breastfeeding mothers.

• Pediatrics: Metoprolol is used in children, primarily for hypertension, with dosing adjusted based on weight.

• Geriatrics: Older adults may be more sensitive to the effects of metoprolol, particularly with respect to hypotension and bradycardia.

13. Therapeutic Uses

• Hypertension: First-line agent for the treatment of high blood pressure, either alone or in combination.

• Angina Pectoris: Used to prevent angina by reducing myocardial oxygen consumption.

• Heart Failure: It is a key part of the pharmacologic management of chronic heart failure with reduced ejection fraction.

• Post-Myocardial Infarction: Helps prevent further complications post-MI and reduces mortality.

14. Monitoring and Follow-Up

• Pre-treatment Monitoring: Blood pressure, heart rate, renal function, and liver function.

• During Treatment: Regular monitoring of heart rate, blood pressure, ECG for arrhythmias, and signs of adverse reactions like dizziness, fatigue, or bradycardia.

15. Overdose Management

• Symptoms of Overdose: Severe bradycardia, hypotension, heart failure, bronchospasm, and central nervous system symptoms like confusion or seizures.

• Treatment Protocols:

  • Administer activated charcoal if overdose is within 1-2 hours.

  • If bradycardia occurs, atropine or a beta-agonist (e.g., isoproterenol) can be used.

  • For severe hypotension, intravenous fluids and vasopressors may be required.

16. Patient Counseling Information

• Key Points to Discuss:

  • Take metoprolol as prescribed, even if you feel well.

  • Do not stop the medication abruptly without consulting your doctor.

  • Inform your healthcare provider if you have any history of asthma, heart conditions, or diabetes.

• Signs/Symptoms Warranting Immediate Medical Attention:

  • Slow heart rate, severe dizziness, fainting, shortness of breath, or swelling of the legs.