Metoprolol + Hydrochlorothiazide

Oral
Hypertension

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.

immediate release tab: Should be taken with food. as metoprolol tartrate
extended release tab: May be taken with or without food. as metoprolol succinate

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).

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.

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.

PO: C

Avoid exposure to direct sunlight and UV light, and consider applying sunscreen when going outdoors.

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.

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.

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.

Alcohol may potentiate the orthostatic hypotensive effect of hydrochlorothiazide.

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).

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.

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

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 3639, Hydrochlorothiazide. https://pubchem.ncbi.nlm.nih.gov/compound/Hydrochlorothiazide. Accessed Feb. 23, 2023.

Store between 15-30°C. Protect from moisture.

Beta-Blockers / Diuretics

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.

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

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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.