Metoprolol + Hydrochlorothiazide


Generic Medicine Info
Indications and Dosage
Oral
Hypertension
Adult: Dosage must be determined by titration of individual components. As substitute for separate dosing of components or as combination when response to single component is suboptimal.

Conventional tab:
Metoprolol tartrate 50 mg and hydrochlorothiazide 25 mg
Metoprolol tartrate 100 mg and hydrochlorothiazide 25 mg
Metoprolol tartrate 100 mg and hydrochlorothiazide 50 mg

Dose range: 100-200 mg/25-50 mg daily as single or in divided doses. Doses may be adjusted according to patient response. If necessary, another antihypertensive agent may be added gradually, initiating with 50% of the usual starting dose of the other agent.

Extended-release tab:
Metoprolol succinate (extended-release) 25 mg and hydrochlorothiazide 12.5 mg
Metoprolol succinate (extended-release) 50 mg and hydrochlorothiazide 12.5 mg
Metoprolol succinate (extended-release) 100 mg and hydrochlorothiazide 12.5 mg

Initially, 25 mg/12.5 mg once daily, may be titrated at intervals of 2 weeks depending on the blood pressure response. Max: 200 mg/25 mg once daily.
Special Patient Group
Metoprolol is primarily metabolised by the CYP2D6 isoenzyme. It observes stereoselective metabolism that is dependent on oxidation phenotype. CYP2D6 is lacking in approx 8% of Caucasians and approx 2% of other populations.

Poor, intermediate, extensive, and ultrarapid metabolisers of metoprolol have been identified and studies confirmed that plasma concentrations of metoprolol correlate with the metaboliser status. Use of metoprolol with CYP2D6 poor metabolisers exhibit several-fold higher plasma concentrations in comparison to extensive metabolisers. Additionally, drugs that inhibit CYP2D6 are likely to increase metoprolol plasma concentration, thereby causing a decrease in cardioselectivity.
Administration
Immediate Release Tab: Should be taken with food. as metoprolol tartrate
Extended Release Tab: May be taken with or without food. as metoprolol succinate
Contraindications
2nd- or 3rd-degree atrioventricular block, sinus bradycardia, sick sinus syndrome (without pacemaker); cardiogenic shock, overt cardiac failure, anuria; severe peripheral arterial circulatory disorders (conventional tab).
Special Precautions
Patient with compensated heart failure, volume depletion, ischaemic heart disease, 1st-degree atrioventricular block, conduction disorders, peripheral vascular disease, Raynaud’s disease, bronchospastic disease, thyroid disease (e.g. hyperthyroidism), diabetes mellitus, history of or familial predisposition to gout, hypercholesterolaemia, myasthenia gravis, untreated pheochromocytoma, history of severe anaphylaxis to allergens, sulfonamide or penicillin allergy; hypercalcaemia. Patient undergoing major surgery. Avoid abrupt withdrawal. Renal and hepatic impairment. Pregnancy and lactation. CYP2D6 poor metabolisers.
Adverse Reactions
Significant: Cardiac failure; photosensitivity, non-melanoma skin cancer (long-term use); bradycardia, sinus pause, heart block, cardiac arrest, gout or hyperuricaemia, electrolyte imbalance (e.g. hypokalaemia, hypochloraemic alkalosis, hypomagnesaemia, hyponatraemia), azotaemia, acute transient myopia, acute angle-closure glaucoma; exacerbated angina pectoris and MI (abrupt withdrawal); new-onset or exacerbation of SLE, arterial insufficiency; increased cholesterol and triglyceride levels, bronchospasm. Rarely, worsening of psoriasis.
Blood and lymphatic system disorders: Agranulocytosis, aplastic anaemia, leucopenia, thrombocytopenia.
Cardiac disorders: Palpitation.
Ear and labyrinth disorders: Vertigo, otalgia, tinnitus.
Eye disorders: Blurred vision.
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, constipation, xerostomia, pancreatitis, digestive disorder.
General disorders and administration site conditions: Fatigue, flu-like symptoms, cold extremities.
Hepatobiliary disorders: Jaundice.
Immune system disorders: Hypersensitivity reactions (including anaphylaxis).
Investigations: Elevated liver enzymes, serum bilirubin.
Metabolism and nutrition disorders: Oedema, anorexia, hyperglycaemia.
Musculoskeletal and connective tissue disorders: Myalgia, muscle spasm.
Nervous system disorders: Drowsiness, headache, dizziness, lethargy, nightmares, short-term memory loss, paraesthesia, restlessness.
Psychiatric disorders: Depression, mental confusion, insomnia.
Renal and urinary disorders: Glycosuria.
Reproductive system and breast disorders: Impotence.
Respiratory, thoracic and mediastinal disorders: Nasopharyngitis, dyspnoea.
Skin and subcutaneous tissue disorders: Diaphoresis, pruritus, rash, purpura, alopecia.
Vascular disorders: Necrotising angiitis, orthostatic hypotension.
Patient Counseling Information
Avoid exposure to direct sunlight and UV light, and consider applying sunscreen when going outdoors.
MonitoringParameters
Monitor blood pressure, heart rate and rhythm, renal function, fluid and electrolyte levels (e.g. Na, K). Assess for signs and symptoms of dizziness and light-headedness, photosensitivity reactions, and skin cancer.
Overdosage
Symptoms: Hypotension, bradycardia or tachycardia, shock, cardiac failure, confusion, dizziness, muscle cramps, weakness, paraesthesia, fatigue, nausea, vomiting, thirst, bronchospasm, fluid and electrolyte loss, hypokalaemia, hyponatraemia, hypochloraemia, alkalosis, raised BUN, polyuria, oliguria, or anuria. Management: Symptomatic and supportive treatment. Induce vomiting, perform gastric lavage, or administer activated charcoal to eliminate content. In case of hypotension, raise the patient’s legs, correct fluid and electrolyte loss, and administer vasopressor (e.g. levarterenol, dopamine) as required. Give β2 agonists or theophylline in cases of bronchospasm. Administer atropine to treat bradycardia; may give isoproterenol cautiously if there is no response to vagal blockade. To combat cardiac failure, administer digitalis glycoside and diuretic. In case of shock resulting from inadequate cardiac contractility, may consider giving dobutamine, isoproterenol, or glucagon.
Drug Interactions
Metoprolol: May increase plasma concentration with strong CYP2D6 inhibitors (e.g. fluoxetine, paroxetine, bupropion, thioridazine, quinidine, propafenone, ritonavir, diphenhydramine, hydroxychloroquine, terbinafine, cimetidine). May cause additive effects with catecholamine-depleting drugs (e.g. reserpine, MAOIs). Increased risk of bradycardia with digitalis glycosides. May increase cardiodepressant effect with general anaesthetics. Metoprolol may reduce the therapeutic effect of epinephrine.
Hydrochlorothiazide: May increase the risk of hypokalaemia with steroids or ACTH. May decrease the arterial response to norepinephrine. May increase effect of tubocurarine. Reduced clearance of lithium thus increases the risk of toxicity. Rarely, concomitant use with methyldopa may increase risk of haemolytic anaemia. Diminished therapeutic effect with NSAIDs. Decreased absorption with colestyramine and colestipol resins.
Food Interaction
Alcohol may potentiate the orthostatic hypotensive effect of hydrochlorothiazide.
Lab Interference
Hydrochlorothiazide: May affect parathyroid function tests; may reduce serum iodine (protein-bound) without signs of thyroid disturbance. May cause false-negative aldosterone/renin ratio (ARR).
Action
Description: Metoprolol competitively blocks β1- receptors and possesses little to no effect on β2- receptors except at higher doses. It does not exhibit membrane stabilising or intrinsic sympathomimetic activity.
Hydrochlorothiazide, a thiazide diuretic, inhibits Na reabsorption in the distal tubules causing increased Na, water, K and hydrogen ions excretion.
Onset: Metoprolol tartrate: Within 1 hour.
Hydrochlorothiazide: Diuresis: Approx 2 hours.
Duration: Metoprolol: Variable (as tartrate); Approx 24 hours (as succinate).
Hydrochlorothiazide: 6-12 hours.
Pharmacokinetics:
Absorption: Metoprolol: Rapidly and completely absorbed from the gastrointestinal tract. Bioavailability: Approx 40-50% (as tartrate); 77% (as succinate). Time to peak plasma concentration: 1.5-2 hours; 10-12 hours (as succinate).
Hydrochlorothiazide: Rapidly and well absorbed from the gastrointestinal tract. Enhanced absorption with food. Bioavailability: 65-75%. Time to peak plasma concentration: Approx 1-5 hours.
Distribution: Crosses the placenta, enters breast milk.
Metoprolol: Widely distributed. Volume of distribution: 3.2-5.6 L/kg. Plasma protein binding: Approx 10-12%, mainly to albumin.
Hydrochlorothiazide: Volume of distribution: 3.6-7.8 L/kg. Plasma protein binding: Approx 40-70%, mainly to albumin.
Metabolism: Metoprolol: Extensively metabolised in the liver by CYP2D6, undergoes first-pass metabolism (approx 50%).
Hydrochlorothiazide: Not metabolised.
Excretion: Metoprolol: Via urine (95%, <5% as unchanged drug; increased to 30-40% in CYP2D6 poor metabolisers). Elimination half-life: 3-4 hours (7-9 hours in CYP2D6 poor metabolisers).
Hydrochlorothiazide: Via urine (≥61% as unchanged drug). Elimination half-life: Approx 5-15 hours.
Chemical Structure

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)


Chemical Structure Image
Hydrochlorothiazide

Source: National Center for Biotechnology Information. PubChem Database. Hydrochlorothiazide, CID=3639, https://pubchem.ncbi.nlm.nih.gov/compound/Hydrochlorothiazide (accessed on Jan. 20, 2020)

Storage
Store between 15-30°C. Protect from moisture.
MIMS Class
ATC Classification
C07CB02 - metoprolol and other diuretics ; Belongs to the class of selective beta-blocking agents in combination with other diuretics. Used in the treatment of cardiovascular diseases.
References
Annotation of FDA Label for Metoprolol and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 24/11/2020.

Annotation of Swissmedic Label for Metoprolol and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 24/11/2020.

Anon. CYP2D6 - Metoprolol (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 24/11/2020.

Anon. Hydrochlorothiazide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 10/09/2020.

Anon. Metoprolol and Hydrochlorothiazide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 10/09/2020.

Anon. Metoprolol. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 10/09/2020.

Anon. Metoprolol. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 10/09/2020.

Buckingham R (ed). Hydrochlorothiazide. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 10/09/2020.

Buckingham R (ed). Metoprolol. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 10/09/2020.

Dutoprol Tablet (Concordia Pharmaceuticals Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 20/11/2020.

Metoprolol Tartrate and Hydrochlorothiazide Tablet (Alembic Pharmaceuticals Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 10/09/2020.

Disclaimer: This information is independently developed by MIMS based on Metoprolol + Hydrochlorothiazide from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2021 MIMS. All rights reserved. Powered by MIMS.com
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