Metoprolol


Thông tin thuốc gốc
Chỉ định và Liều dùng
Intravenous
Adjunct in the early management of acute myocardial infarction
Adult: Within 12 hours of the onset of chest pain: 5 mg at 2-minute intervals to a total of 15 mg as determined by heart rate and blood pressure. Initiate oral therapy 15 minutes after the last inj in patients who have received the full IV dose.

Intravenous
Control of arrhythmias during anaesthesia, Prophylaxis of arrhythmias at induction of anaesthesia
Adult: 2-4 mg via slow inj, may give additional doses of 2 mg as necessary. Max total dose: 10 mg.

Intravenous
Cardiac arrhythmias
Adult: For control of cases, particularly supraventricular tachyarrhythmias: Initially, up to 5 mg given at a rate of 1-2 mg/min, may be repeated, if necessary, at 5-minute intervals to a total dose of 10-15 mg.

Oral
Angina pectoris
Adult: As conventional tab (metoprolol tartrate): 50-100 mg bid or tid. Adjust dose according to individual requirements. Max: 400 mg daily. As extended-release tab/cap (metoprolol succinate): Initially, 100 mg once daily, may be increased gradually at weekly intervals until satisfactory response is achieved. Max: 400 mg daily.

Oral
Hypertension
Adult: As conventional tab (metoprolol tartrate): Monotherapy or in combination with other antihypertensive agents: Initially, 100 mg daily as a single or in 2 divided doses, may be increased at weekly intervals according to response. Maintenance: 200 mg daily as a single or in divided doses. Max: 400 mg daily. As extended-release tab/cap (metoprolol succinate): Initially, 25-100 mg once daily, may be increased at weekly (or longer) intervals according to patient response. Max: 400 mg daily.

Oral
Adjunct in hyperthyroidism
Adult: As conventional tab (metoprolol tartrate): 50 mg 4 times daily. Reduce dosage progressively as euthyroid state is achieved. Adjust dose according to individual requirements. Max: 400 mg daily.

Oral
Prophylaxis of migraine
Adult: As conventional tab (metoprolol tartrate): 100-200 mg daily in divided doses. Adjust dose according to individual requirements. Max: 400 mg daily.

Oral
Heart failure
Adult: As extended-release tab/cap (metoprolol succinate): Initially, 12.5-25 mg once daily, may be increased gradually as tolerated, at intervals of 2 weeks. Max: 200 mg daily.

Oral
Cardiac arrhythmias
Adult: As conventional tab (metoprolol tartrate): 50 mg bid or tid, may be increased up to 300 mg daily in divided doses, as necessary. Adjust dose according to individual requirements. Max: 400 mg daily.

Oral
Acute myocardial infarction
Adult: As conventional tab (metoprolol tartrate): Early intervention: In patients who tolerate the full IV metoprolol dose: 50 mg 6 hourly, initiate 15 minutes after the last IV inj and continue for 48 hours. Usual maintenance: 200 mg daily in divided doses. In patients who fail to tolerate the full IV dose: Reduce dose or give half of the recommended dose. Adjust dose according to individual requirements. Late intervention: In patients not given IV metoprolol as part of early management: 100 mg bid as soon as clinical condition allows. Continue therapy for at least 3 months.
Nhóm bệnh nhân đặc biệt
Pharmacogenomics:

Metoprolol is metabolised primarily by CYP2D6 isoenzyme. It exhibits stereoselective metabolism that is dependent on oxidation phenotype. CYP2D6 is lacking in approx 8% of Caucasians and approx 2% of most other populations.

Poor, intermediate, extensive, and ultrarapid metabolisers of CYP2D6 have been identified and several studies confirmed that plasma concentrations of metoprolol correlate with the metaboliser status. CYP2D6 poor metabolisers exhibit several-fold higher plasma concentrations of metoprolol in comparison to normal metabolisers. Additionally, concomitant use of drugs that inhibit CYP2D6 are likely to increase metoprolol plasma concentrations, thus decreasing the cardioselectivity of the drug.

Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DWPG) Guideline as of November 2018:
Phenotype Implications Recommendations
CYP2D6 intermediate metabolisers Reduced conversion of metoprolol to inactive metabolites. However, clinical consequences are limited primarily to the event of asymptomatic bradycardia. No changes in dose or monitoring are recommended when initiating therapy. However, if a gradual reduction in heart rate is desired or in case of symptomatic bradycardia, dose may be increased in smaller steps and/or give no more than 50% of the standard dose.
CYP2D6 poor metabolisers Reduced conversion of metoprolol to inactive metabolites. However, clinical consequences are limited primarily to the event of asymptomatic bradycardia. No changes in dose or monitoring are recommended when initiating therapy. However, if a gradual reduction in heart rate is desired or in case of symptomatic bradycardia, dose may be increased in smaller steps and/or give no more than 25% of the standard dose.
CYP2D6 ultrarapid metabolisers Increased conversion of metoprolol to inactive metabolites which may increase dose requirement. However, with a target dose of 200 mg daily, no effect on the blood pressure and on the reduction of heart rate were observed. The maximum dose for the indication is recommended as the target dose. If the effect is not achieved at the target dose, consider increasing the dose based on effectiveness and adverse effects up to 2.5 times the standard dose or consider an alternative β-blocker, such as bisoprolol or carvedilol (for heart failure), atenolol or bisoprolol (for other indications).

Suy gan
Dosage reduction may be necessary.
Chống chỉ định
2nd- or 3rd-degree atrioventricular block, overt or unstable decompensated cardiac failure, clinically relevant sinus bradycardia, sick-sinus syndrome (without pacemaker), severe peripheral arterial disease, cardiogenic shock, hypotension, untreated phaeochromocytoma, metabolic acidosis; severe asthma; MI complicated with severe sinus bradycardia (heart rate: <45 beats/min), significant 1st-degree heart block (P-R interval ≥0.24 seconds), systolic blood pressure of <100 mmHg, and/or moderate to severe heart failure.
Thận trọng
Patient with history of severe anaphylaxis to allergens, diabetes mellitus, compensated heart failure, 1st-degree atrioventricular block, poor cardiac reserve, bronchospastic disease (who do not respond to or are intolerant of other treatment), psoriasis, myasthenia gravis, peripheral vascular disease, Prinzmetal's angina, thyroid disease. Patient undergoing surgery. Avoid abrupt withdrawal; chronic therapy must not be routinely withdrawn before major surgery. May mask the signs and symptoms of hypoglycaemia and hyperthyroidism. Hepatic impairment. Elderly. Pregnancy and lactation. CYP2D6 poor, intermediate, and ultrarapid metabolisers.
Tác dụng không mong muốn
Significant: Bradycardia (including sinus pause, heart block, and cardiac arrest); may precipitate or aggravate symptoms of arterial insufficiency (in patients with peripheral vascular disease), worsening heart failure (particularly during up-titration of metoprolol succinate).
Cardiac disorders: Palpitations.
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain, constipation.
General disorders and administration site conditions: Fatigue.
Nervous system disorders: Dizziness, headache.
Psychiatric disorders: Depression, insomnia, nightmares.
Respiratory, thoracic and mediastinal disorders: Dyspnoea on exertion, bronchospasm.
Skin and subcutaneous tissue disorders: Pruritus, rash.
Vascular disorders: Orthostatic hypotension (occasionally with syncope), cold extremities.
IV/Parenteral/PO: C
Chỉ số theo dõi
Monitor blood pressure, heart rate; ECG (with IV use), heart rhythm (with oral use).
Quá liều
Symptoms: Severe hypotension, bronchospasm, convulsions, nausea, vomiting, sinus bradycardia, atrioventricular block, MI, heart failure, cardiogenic shock, cardiac arrest, cyanosis, hypoglycaemia, impairment of consciousness, coma, and occasionally hyperkalaemia. Management: Symptomatic and supportive treatment. Generally, the patient is managed in an intensive care setting with continuous monitoring of heart function, blood gases, and blood biochemistry. Induce vomiting or perform gastric lavage if within 4 hours after ingestion and/or administer activated charcoal in case of potentially fatal oral overdose. Assess the need for atropine, adrenergic-stimulating agents, or pacemaker to treat conduction disorders and bradycardia. IV vasopressor infusions (e.g. norepinephrine, dopamine) may be given for hypotension. Administer β2-agonist and/or a theophylline derivative to treat bronchospasm. Control seizures with diazepam. Administer digitalis glycoside and diuretic for cardiac failure. Consider dobutamine, isoproterenol, or glucagon in case of shock resulting from inadequate cardiac contractility.
Tương tác
Additive effects with catecholamine-depleting drugs (e.g. reserpine). Increased plasma concentration with CYP2D6 inhibitors (e.g. fluvoxamine, fluoxetine, paroxetine, sertraline, bupropion, clomipramine, desipramine, chlorpromazine, fluphenazine, haloperidol, thioridazine, propafenone, ritonavir, diphenhydramine, hydroxychloroquine, quinidine, terbinafine, cimetidine). Reduced plasma concentration with CYP2D6 inducers (e.g. rifampicin). May result in excessive bradycardia when given with digitalis glycosides, clonidine, diltiazem, verapamil. May enhance cardiodepressant effect with inhalation anaesthetic drugs. Enhanced hypotensive effect with other antihypertensive agents or agents that may reduce blood pressure (e.g. TCAs, barbiturates, phenothiazines). Metoprolol may enhance the rebound hypertension that can follow the withdrawal of clonidine. Reduced antihypertensive effects with NSAIDs (e.g. indometacin). May enhance the vasoconstrictive action of ergot alkaloids.
Tương tác với thức ăn
Food increases absorption.
Tác dụng
Description: Metoprolol selectively inhibits β1-adrenergic receptors within the myocardium, thus inhibiting response to adrenergic stimuli. It reduces heart rate and cardiac output at rest and during exercise, decreases myocardial contractility, reduces systolic blood pressure during exercise, and decreases reflex orthostatic tachycardia. It does not exhibit membrane stabilising or intrinsic sympathomimetic activity. At higher concentrations, metoprolol also inhibits β2-adrenergic receptors within the bronchial and vascular smooth muscle.
Onset: Oral: Within 1 hour (immediate-release); IV: Approx 20 minutes (when infused over a 10-minute period).
Duration: Oral: Dose-dependent (immediate-release); approx 24 hours (extended-release).
Pharmacokinetics:
Absorption: Rapidly and completely absorbed from the gastrointestinal tract. Bioavailability: Approx 40-50% (immediate-release); 77% relative to immediate-release (extended-release). Increased bioavailability with food. Time to peak plasma concentration: 1.5-2 hours.
Distribution: Widely distributed. Crosses the placenta and blood brain barrier; enters breast milk (small amounts). Volume of distribution: 3.2-5.6 L/kg. Plasma protein-binding: Approx 10-12% to serum albumin.
Metabolism: Extensively metabolised in the liver primarily by CYP2D6 isoenzyme, and undergoes oxidative deamination, O-dealkylation followed by oxidation, and aliphatic hydroxylation; undergoes first-pass effect (approx 50%).
Excretion: Via urine (95%, <5-10% as unchanged drug; increased to 30-40% in CYP2D6 poor metabolisers). Elimination half-life: 3-4 hours; 7-9 hours (in CYP2D6 poor metabolisers).
Đặc tính

Chemical Structure Image
Metoprolol_01

Source: National Center for Biotechnology Information. PubChem Database. Metoprolol, CID=4171, https://pubchem.ncbi.nlm.nih.gov/compound/Metoprolol (accessed on Jan. 22, 2020)

Bảo quản
Tab/IV inj: Store between 15-30°C. Protect from light and heat (IV inj). Protect from moisture (tab). Cap: Store between 20-25°C.
Phân loại MIMS
Thuốc trị đau nửa đầu / Thuốc chẹn thụ thể bêta
Phân loại ATC
C07AB02 - metoprolol ; Belongs to the class of selective beta-blocking agents. Used in the treatment of cardiovascular diseases.
Tài liệu tham khảo
Annotation of DPWG Guideline for Metoprolol and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 13/01/2022.

Annotation of FDA Label for Metoprolol and CYP2D6. https://www.pharmgkb.org. Pharmacogenomics Knowledgebase (PharmGKB). Accessed 13/01/2022.

Annotation of Swissmedic Label for Metoprolol and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 13/01/2022.

Anon. CYP2D6 - Metoprolol (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 13/01/2022.

Anon. Metoprolol. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 03/11/2021.

Anon. Metoprolol. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 03/11/2021.

Betaloc 1 mg/mL Solution for Injection (Recordati Ireland Ltd.). MHRA. https://products.mhra.gov.uk. Accessed 03/11/2021.

Betaloc Tablet (AstraZeneca Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 13/01/2022.

Buckingham R (ed). Metoprolol. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 03/11/2021.

Joint Formulary Committee. Metoprolol Tartrate. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 03/11/2021.

Kapspargo Capsule (Sun Pharmaceutical Industries, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 13/01/2022.

Lopressor Tablet (Validus Pharmaceuticals LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 13/01/2022.

Metoprolol Tartrate 25 mg Tablets (Zentiva Pharma UK Limited). MHRA. https://products.mhra.gov.uk. Accessed 03/11/2021.

Metoprolol Tartrate Injection (Hospira, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 03/11/2021.

Toprol XL Tablet (Aralez Pharmaceuticals US Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 13/01/2022.

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