Metoprolol Succinate - A Comprehensive Review of Its Uses, Side Effects, Precautions, Interactions, and Warnings

Overview:

Metoprolol succinate belongs to a group of medicines called beta-blockers. These are beta-adrenergic blocking agents that reduce blood pressure. Metoprolol succinate acts by relieving heart overload and allows it to beat slowly and with less force. This is done by blocking the effects of adrenaline (also known as epinephrine, a hormone that raises heart rate and blood pressure). Metoprolol succinate is Food and Drug Administration (FDA) approved to treat angina, hypertension, and myocardial infarction. The beta-blocker also has a black box warning, as it is known to aggravate symptoms such as shortness of breath or fast breathing associated with activities or when lying down with heart failure in some patients. Metoprolol is available only on a doctor’s prescription.

How Does Metoprolol Succinate Work?

Metoprolol is a cardioselective beta-1- blocker that is commonly employed as succinate and tartrate derivatives. This depends on the design of their formulation - immediate release or extended release. The beta-1-adrenergic receptor blocker inhibits specific cardiac cells while having a negligible effect on beta-2 receptors. The inhibition decreases cardiac output by producing negative chronotropic increases heart rate and rhythm) and inotropic (increases contractility) effects. This results in slower heartbeats and decreases blood pressure. The lowered blood pressure increases the flow of blood and oxygen to the heart. Metoprolol succinate extended-release tablets are formulated to provide a controlled and predictable release of Metoprolol.

Uses:

• Metoprolol can be used to treat high blood pressure (hypertension) alone or in combination with other medications. High blood pressure damages the functioning of the organs such as the brain, heart, blood vessels, kidneys, and various parts of the body.

• The drug may be used to prevent angina (chest pain that is caused as a result of the restricted blood flow to the heart) and is often prescribed for people with cardiovascular conditions or who have had a heart attack.

• Metoprolol succinate is associated with improved survival in patients with ischemic heart failure (a life-threatening cardiac condition characterized by reduced cardiac output).

Limitations:

• Metoprolol succinate cannot be used to prevent heart attacks.

• The drug can cause dizziness and drowsiness and should not be taken while driving or operating heavy machinery.

• Metoprolol can further make the symptoms of heart failure worse, especially while the dose is being adjusted or stopped.

Dosage:

Route of Administration- Oral.

Dosage Strengths -

• 25 mg.

• 50 mg.

• 100 mg.

• 200 mg.

Dosage Forms -

• Extended-Release Capsules - The recommended starting adult dose for high blood pressure is 25 mg to 100 mg once a day. The dose should not be more than 400 mg per day.

• Tablets - Starting dose is 100 mg per day and is usually prescribed for a single dose or sometimes, in divided doses.

Special Considerations:

• Pregnancy - The use of Metoprolol succinate is contraindicated during pregnancy, especially in the third trimester, as it may cause symptoms such as slow heart rate and low blood sugar in the baby. The drug is a Food and Drug Administration (FDA) pregnancy category C drug.

• Lactation - Studies on the use of Metoprolol during breastfeeding have shown no adverse reactions in infants. Small amounts of drugs can be found in breast milk.

• Pediatric Patients - Metoprolol succinate can be given to children six years and above. The drug should be administered cautiously as it can cause low heart rate and lethargy.

• Geriatric Patients - Beta-blockers should be administered cautiously in people over 60 years of age. These patients can have physiologic changes, including low cardiac output, reduced renal blood flow, and low drug clearance.

• Renal Impairment - Therapy with Metoprolol succinate should be administered cautiously in those with renal impairment as the drug may reduce glomerular filtration rate and cardiac output. This may further exacerbate renal dysfunction.

• Hepatic Impairment - Metoprolol has been associated with cases of drug-induced liver injury. The drug may show a rise of serum aminotransferase, which may be a sign of hepatic damage or liver disease.

Warnings and Contraindications:

Contraindications

Metoprolol succinate is contraindicated in the following cases:

• Bradyarrhythmia - Beta-blockers such as Metoprolol succinate is contraindicated in patients with sinus bradyarrhythmia (slow heartbeat). The use of these drugs may exacerbate the condition.

• Hypotension - The use of Metoprolol succinate is contraindicated in patients with low blood pressure or a life-threatening condition like cardiogenic shock (when the heart is not able to pump efficiently enough blood and oxygen to organs, such as the brain, kidney, or lungs). The beta-blocker may further depress the cardiac output and blood pressure.

• Congestive Heart Failure - Therapy with Metoprolol succinate should not be given in patients with chronic conditions such as congestive heart failure, where the heart is not able to pump enough blood. The drug may be administered cautiously by compensating for the inotropic effect with the use of Digitalis, diuretics, and acetylcholine inhibitors.

Warnings and Precautions

• Anaphylactic Reaction - Metoprolol succinate may precipitate serious allergic reactions (anaphylaxis) with symptoms such as rash, itching, swelling of the face and throat or tongue, and troubled breathing.

• Heart Failure - Initiation of beta-blockers therapy may worsen heart failure. The drug should be started at a low dose. Metoprolol succinate cannot help to prevent heart attacks in people.

• Diabetes - Therapy with beta-blockers may mask the symptoms of low blood sugar levels in the blood (hypoglycemia), such as tremors, abnormally rapid heart rate (tachycardia), and changes in blood pressure. Metoprolol succinate should be administered cautiously in patients with known diabetes or predisposed to spontaneous hypoglycemia (results from the body producing too much insulin after a meal in people without diabetes).

• Hemodialysis - Parameters such as heart rate and blood pressure, and cardiac output that form the hemodynamic status should be closely monitored by the doctor, before and after Metoprolol succinate treatment in patients requiring hemodialysis. This will help to avoid sudden falls in blood pressure.

• Liver Disease - Metoprolol is primarily metabolized by the liver. The drug should be administered cautiously in patients with liver disease, as they are at greater risk for adverse effects due to delayed drug clearance. These patients may require dosage adjustments.

• Glaucoma - Patients with glaucoma may require dose adjustments in their ophthalmic regimen following treatment with Metoprolol. The drug may lower intraocular pressure and should be used cautiously in patients with glaucoma.

• Hyperthyroidism - Cessation of beta-blocker therapy should occur gradually throughout one to two weeks. Abrupt discontinuation of Metoprolol in patients with hyperthyroidism may exacerbate thyrotoxicosis (high levels of circulating thyroid hormone in the body) or precipitate a thyroid storm that may be life-threatening.

For Patients

Hypertension:

Raised blood pressure is a common medical condition that significantly affects the body’s arteries and increases the risks to organs such as the heart, brain, and kidneys. Blood pressure is defined as the force applied by the circulating blood against the walls of the arteries (blood vessels circulating oxygen-rich blood) in the body. Hypertension happens when the pressure exerted by blood is too high, and the reading is 130 mm Hg (millimeter of mercury) or higher.

Why Is Metoprolol Succinate Prescribed for Hypertension?

Metoprolol succinate is a beta-blocker that affects the response to the nerve impulses, such as epinephrine, in certain body parts, like the heart. This results in a slow heartbeat and a decrease in blood pressure. Lowering the blood pressure increases blood and oxygen flow to the heart and allows the heart to pump with less force. Metoprolol succinate is good for treating high blood pressure.

Facts One Should Know About Metoprolol Succinate:

• Treatment with Metoprolol succinate can often be long-term. The medication should not be stopped suddenly, as it can worsen the condition and may cause chest pain, heart attack, or irregular heartbeat. The dosage of Metoprolol should be gradually decreased over one to two weeks.

• Metoprolol may cause dizziness, which mostly happens after rising from a sitting or lying position.

• Lifestyle changes like a low-fat diet, exercise, and not smoking allow the medicine to work better.

• Both Metoprolol succinate and Metoprolol tartrate can be used to treat hypertension. It is, however, important not to substitute one for the other. Both drugs come in different forms, are approved for different uses, and may cause slightly different side effects.

How Should One Take Metoprolol Succinate?

• Metoprolol succinate is taken once or twice a day.

• It is usually taken with meals or just after a meal.

• The drug should be taken at the same time each day.

• Metoprolol succinate is usually started on a low dose of 25 mg and is gradually increased.

• It may take more than two weeks to show the full benefits of the drug, as seen in a blood pressure reading.

• Do not stop the medicine suddenly without talking to the doctor.

• Metoprolol succinate is used for long-term treatment and requires regular blood pressure monitoring to ensure the medication works.

What Should the Patient Discuss With the Doctor Before Beginning Metoprolol Succinate Therapy?

• Allergies - Inform the physician if one has ever had an allergic reaction to Metoprolol or other ingredients in the formulation. The medication may contain inactive ingredients, which can cause allergic reactions.

• Medical History - The patient must always inform the treating doctor of his illnesses, such as diabetes, blood circulation problems (such as Raynaud’s disease, peripheral vascular disease), bronchospastic diseases, myocardial infarction, and impaired renal or hepatic function.

• Drug History - Always give the treating doctor a complete list of the prescription and non-prescription medications that one may be taking, including any herbal supplements, nutritional supplements, and vitamins.

• Pregnancy - If one is pregnant or planning to get pregnant any time soon, it is important to inform the doctor. The use of Metoprolol succinate may harm the fetus and the mother and should be used only when needed. Using Metoprolol succinate during the third trimester of pregnancy may increase the risk of hypotension and low blood sugar level. If one gets pregnant while on Metoprolol succinate, inform the doctor as soon as one finds out.

• Lactation - The doctor must know if one is breastfeeding. There is a possibility of Metoprolol succinate passing into the breastmilk. It is best to avoid it during nursing as beta-blockers have the potential to produce serious adverse reactions.

• Surgical Treatment - It is important to brief the dental doctor about medicines (Metoprolol succinate) before the dental procedures, as certain anesthetics may increase the risk of side effects.

• Alcohol - Patients should inform the doctor if they are heavy alcohol drinkers, as it can increase blood pressure and exacerbate the side effects.

Is Metoprolol Succinate Safe?

Metoprolol succinate is a generally very safe drug and FDA-approved medication for the long-term treatment of hypertension. The doctor may advise one to monitor the blood pressure daily at home or between office hours to check the drug's effectiveness. When visiting a doctor, he will do routine blood tests to check the functioning of one’s liver and kidneys. People may experience problems if they happen to abruptly stop taking the drugs, as this can lead to chest pain, increased blood pressure, and heart attack.

Effectiveness of Metoprolol Succinate:

The antihypertensive efficacy of Metoprolol succinate is well-established for long-term treatment. It also lowers the risk of hospitalization and death in people with heart failure.

Metoprolol succinate is very effective when used alone in patients with isolated systolic hypertension. Studies have found a great reduction in blood pressure after six months of treatment. Metoprolol succinate has a greater degree of selectivity for beta-adrenergic receptors than other agents in this class. It has a unique vasodilating effect, which is advantageous for a hypertensive population with diabetes and other vascular diseases. The drug also has better tolerability than other agents in this class.

Side Effects a Patient Can Expect with Metoprolol Succinate:

The common side effects that occur with the use of Metoprolol succinate are as follows:

• Dizziness.

• Tiredness.

• Slow heart rate.

• Headache.

• Diarrhea.

• Nausea.

• Stomach pain.

The serious side effects may include,

• Chest pain.

• Very slow heart rate.

• Severe dizziness.

• Fainting.

• Lightheadedness.

• Extreme tiredness.

• Swelling in the hands, arms, feet, ankles, or legs.

• Trouble breathing.

• Rapid weight gain.

• Cold feeling in hands and feet.

Can One Stop Taking Metoprolol Succinate Without the Doctor's Consent?

• One should never stop taking Metoprolol succinate without first talking to the doctor. Consult the physician or visit the emergency room if one experiences any side effects that require immediate attention.

• Do not skip the dose or stop taking Metoprolol succinate suddenly. This can worsen the condition or cause serious problems, including heart attacks. The patient is instructed to gradually taper the dose by the doctor.

• Remember that one must continue taking Metoprolol succinate, regardless of how well one responds to it unless the doctor explicitly mentions otherwise. The drug is usually meant for long-term use and should not be stopped even if one responds well.

Dietary Restrictions to Consider When Taking Metoprolol Succinate:

The patient may continue to follow their regular diet unless the doctor asks them to change it. No dietary restrictions are needed. The drug may be taken with or without food.

• Caffeine-Containing Foods - Avoid taking caffeine-containing food items and beverages such as tea, coffee, and chocolates while taking Metoprolol succinate. Caffeine can decrease the effectiveness of the drug.

• High Potassium Foods - The patient should limit the consumption of high potassium-containing foods such as bananas, papaya, tomatoes, and avocado.

Storage of Metoprolol Succinate:

• Store Metoprolol Succinate at room temperature in a closed container, away from heat, moisture, and direct light.

• Metoprolol succinate tablets should be stored in the original packaging or container with a tightly closed lid.

• Keep this drug far from the reach of children and pets.

Disposal of Metoprolol Succinate:

• Metoprolol should not be disposed of by flushing or throwing it out with regular garbage.

• The patient may dispose of Metoprolol through the local medicine take-back program, which can be accessed or learned more about through the local pharmacist.

• If the patient does not have access to a medicine take-back program, ask the local pharmacist about other drug disposal options.

Overdose:

• If the patient overdoses, contact the doctor immediately and do not take another tablet until the doctor tells the patient to do so.

• If the patient experiences severe side effects like seizures or breathing difficulty, a bystander or family member should take them to the emergency room or contact local poison control services.

For Doctors

Indications:

Metoprolol succinate is indicated for the following purposes:

• Metoprolol succinate is prescribed for treating high blood pressure ( hypertension). The drug can be used as monotherapy or may be combined with other antihypertensive agents.

• It is also indicated in the long-term treatment of angina pectoris, which is caused due to reduced blood flow to the heart.

• The drug can be used to treat stable, symptomatic class II and III heart failure of ischemic, hypertensive, or cardiomyopathy origin. It helps to decrease the rate of cardiovascular mortality and hospitalization for heart failure.

• Metoprolol succinate can also be used to prevent migraine.

Pharmacology of Metoprolol Succinate:

Description

Metoprolol succinate is a beta-1-cardioselective adrenoceptor-blocking agent. It is available as an extended-release tablet.

• It is a white, crystalline powder with a molecular weight of 652.8. It s freely soluble in water

• The tablets comprise a multiple-unit system containing Metoprolol succinate in a multitude of controlled-release pellets. Each pellet acts as a separate drug delivery unit.

• The chemical name is 1-(isopropylamine)3-[p-(2-methoxyethyl)phenoxy}-2-propanol succinate.

Components-

1. Active Ingredients.

Metoprolol succinate.

2. Inactive Ingredients

• Silicon dioxide.

• Cellulose compounds.

• Sodium stearyl fumarate.

• Polyethylene glycol.

• Titanium dioxide.

• Paraffin.

Clinical Pharmacology:

Mechanism of Action

The beta-blocking activity of Metoprolol is shown by

• Reducing the heart rate and amount of blood that is pumped by the heart (cardiac output) at rest and upon exercise.

• Reduction of systolic blood pressure upon exercise.

• Inhibition of isoproterenol-induced tachycardia.

• Reduction of reflex orthostatic tachycardia.

Pharmacodynamics:

Single And Repeated Doses - Reduces heart rate and blood pressure at rest and during exercise in hypertensive patients.

Therapeutic Dose - Metoprolol succinate is devoid of alpha-adrenergic antagonism. It has a long duration of action, and its effects can be seen 48 hours after stopping the medication.

Pharmacokinetics:

• Mean Cmax- Bioavailability is 100 % when administered intravenously and 40 % when taken orally.

• Median Tmax- 20 minutes of intravenous administration and one to two hours after oral administration. The bioavailability of the drug may be enhanced by the presence of food.

[Cmax- Maximum concentration achieved by a drug in the blood, cerebrospinal fluid, or target organ after administration of a dose]

[Tmax- Time taken for a drug to reach maximum concentration after administration of a dose]

Pharmacokinetic Changes -

The dose is to be adjusted to individual requirements due to variations in the rate of metabolism.

A. Distribution

• Steady-state Plasma Levels - The concentration of unchanged Metoprolol succinate is 4.2 liter per kilogram.

• Time to Approach Steady-State Levels - Three to seven hours.

• Binding to Plasma Proteins - The drug is not highly bound to plasma proteins, and only about 11 % of the administered drug is found bound. It is mainly bound to serum albumin.

B. Metabolism

• Metabolic Processes - Glucuronidation and CYP2D6 mediated hydroxylation, N-dealkylation, and oxidation.

• Active Metabolites - Aromatic hydroxyl and acyclic oxide metabolites.

• Inactive Metabolites - Alpha-Hydroxymetoprolol, O-Desmethyl Metoprolol, and Deisopropylmetoprolol.

C. Excretion

• Recovery of Metoprolol Succinate - Less than 5 % of an oral dose is recovered unchanged in the urine.

• After One Week Of Administration - 85 % of the dose is excreted in the urine.

• Mean elimination half-life - One to two days.

Special Considerations

Metoprolol succinate carries a boxed warning. The drug may worsen chest pain or heart attack if stopped suddenly.

• Hypotension - Metoprolol succinate can cause negative inotropic and chronotropic effects on the heart (change in heartbeat and rhythm) and can be likely to further depress cardiac output and blood pressure, which can be fatal.

• Hepatic Impairment- Metoprolol succinate is metabolized by the liver. The decreased drug clearance seen in patients with liver disease can increase the risk of adverse effects from Metoprolol. Dosage adjustments may be necessary.

• Bronchospastic Disease - Metoprolol succinate should be administered cautiously in patients with the bronchospastic disease or those who do not respond or can tolerate other antihypertensive drugs. The lowest possible dose should be used in these patients.

Alcohol - Combining ethanol with Metoprolol may have additive effects in lowering blood pressure and cause symptoms such as headache, dizziness, and change in heart rate.

Drug Interactions:

• Catecholamine Depleting Drugs - Drugs such as Reserpine and monoamine oxidase (MAO) inhibitors may have additive effects when combined with beta-blocking agents such as Metoprolol succinate. The patient must be monitored for signs of hypotension or bradycardia that may produce symptoms like vertigo, syncope, or postural hypotension.

• Calcium Channel Blockers - Medicines such as Digitalis glycosides, Diltiazem, and Verapamil may slow atrioventricular conduction (a condition when the conduction of the atrial impulses to the ventricles is delayed) and decrease the heart rate.

• CYP2D6 Inhibitors - Drugs such as Quinidine, Fluoxetine, and Propafenone can increase the Metoprolol concentration in the plasma. This may decrease the binding of the beta-blocker.

• Other Antihypertensives - Combining Metoprolol succinate with other antihypertensives such as Chlorthalidone and Indapamide can further lower blood pressure. This can cause severe dizziness and drowsiness.

• Antidepressants - Using Metoprolol succinate along with antidepressants such as Fluoxetine can cause changes in blood pressure.

• Multivitamins with Minerals - Taking Metoprolol together with multivitamins with minerals may decrease the effects of the drug. The administration time of them should be at least two hours apart.

What Have Clinical Trials Shown Concerning Metoprolol Succinate?

Aim of Trial 1:

The main objective of the study was to evaluate the efficacy of controlled-release Metoprolol succinate for the treatment of heart failure with preserved ejection fraction (HFpEF).

• The study was an investigator-initiated, randomized, double-blind, placebo-controlled, 14-week pilot study with Metoprolol succinate as a study drug.

• Drug titration was performed with optimal upward titration of doses ranging from 25 mg to 100 mg.

• Twenty patients were enrolled in each treatment arm.

Endpoint - Clinical, echocardiographic, biochemical, and quality of life were included in the study. The mean change in various echocardiographic and biochemical Parameters was statistically insignificant.

Results - There was an improvement in some quality of life parameters observed. No serious adverse events were seen. Metoprolol succinate has some beneficial role in HFpEF, as reflected by improvement in some parameters. The study highlighted the need for a larger study with longer follow-ups.

Aim of Trial 2:

To evaluate the efficacy, tolerability, and blood pressure lowering effect of extended-release Metoprolol succinate in children six to sixteen years of age with established hypertension.

• Patients were randomized to one of four treatment arms - placebo extended-release Metoprolol 0.2 milligram per kilogram.

• Data were analyzed on 140 intent-to-treat patients.

• Following four weeks, mean changes in sitting blood pressure in placebo were 1.9 mmHg, and extended-release Metoprolol was 3.1 mmHg.

• There were no serious adverse events requiring drug discontinuation among patients receiving active therapy.

End Point - Extended-release Metoprolol significantly reduced systolic blood pressure (1.0 mg per kg dose), dose reduced diastolic blood pressure at 2.0 mg per kg, and showed a statistically significant dose-response relationship for the placebo-corrected change from baseline.

Result - These data indicate that extended-release Metoprolol is an effective and well-tolerated treatment for hypertension in children.

Aim of Trial 3:

A factorial study of a combination of hypertension treatment with Metoprolol succinate extended-release ER) and Felodipine extended-release - A combination trial.

• A multicenter, randomized, placebo-controlled, unbalanced factorial study. It included a four to five-week single-blinded placebo, nine-week, double-blind treatment, as well as a two-week double-blind, down-titrated period.

• Patients were randomized to one of 16 treatment groups - extended-release Metoprolol succinate, extended-release Felodipine, extended-release, or placebo.

• At baseline, treatment groups were well-balanced. The mean sitting blood pressure was 152.6 mm Hg.

• Monotherapy with extended-release Metoprolol succinate induced dose-related reductase in sitting systolic/diastolic blood pressure 8.1 to 9.7 mm Hg and 7.7 to 14.0 mm Hg for Felodipine. The combination reflected additive effects of 13.8 to 19.8 mm Hg.

• The decline in the placebo group was 2.1 mm Hg.

• Adverse events that may lead to discontinuation of the treatment with Metoprolol were peripheral edema (4 %), headache (2 %), and fatigue (1 %).

End Point - All combinations were more effective than their components (but extended-release Metoprolol succinate and Felodipine). When compared with higher doses of the individual agents, the low-dose combination was approximately as effective.

Result - The antihypertensive effects of ER Metoprolol succinate and ER Felodipine are dose-related, and when given in combination, their blood pressure-lowering effects are additive over a wide dose range. Low-dose combination therapy is comparable in effectiveness to high-dose monotherapy but is better tolerated.

Patient Counseling Information:

Administration Instructions

• Take Metoprolol succinate only as prescribed by the doctor.

• This drug may be taken with or without food.

• Swallow these tablets and do not crush, split, or chew them.

• Do not stop taking Metoprolol succinate abruptly.

Complications or Side Effects

• Pregnancy- A small study has shown that the use of Metoprolol succinate can cause birth defects or preterm birth. The drug, when taken in late pregnancy, can cause babies to have symptoms such as slow heart rate and low blood sugar.

• Hypersensitivity- Metoprolol succinate is contraindicated in people who have allergic reactions to the drug or its constituents. The user may be associated with heightened reactivity to allergens and may affect the frequency and severity of attacks.

• Bradyarrhythmias - Metoprolol therapy, when given for the long term, can cause elevated concentration in the blood and increase the risk of bradycardia. This interferes with slow action potential generation and atrioventricular conduction and can have chronotropic and inotropic effects.

• Asthma - Small doses of Metoprolol succinate help to avoid high plasma levels. Patients with bronchospastic disease, such as asthma, should not receive beta-blocker and should take bronchodilators while taking Metoprolol.

• Diabetes - Metoprolol succinate masks symptoms of hypoglycemia, such as blood pressure changes and tremors, and inhibits catecholamine-mediated glycogenolysis. This potentiates insulin-induced hypoglycemia and delays every normal blood glucose level.

• Hyperthyroidism - Abrupt cessation of Metoprolol succinate can exacerbate thyrotoxicosis or precipitate a thyroid storm. The drug dosage should be gradually reduced over two weeks.