Metodura ZNT

Uses

ln the management of hypertension and angina pectoris. Cardiac arrhythmias, especially supraventricular tachyarrhythmias. Adjunct to the treatment of hyperthyroidism. Early intervention with Metodura ZNT in acute myocardial infarction reduces infarct size and the incidence of ventricular fibrillation. Pain relief may also decrease the need for opiate analgesics. Metodura ZNT has been shown to reduce mortality when administered to patients with acute myocardial infarction.

Metodura ZNT is also used to associated treatment for these conditions: Angina Pectoris, Atrial Fibrillation, High Blood Pressure (Hypertension), Migraine, Myocardial Infarction, Tachycardia, Supraventricular, Thyroid Crisis, Acute hemodynamically stable Myocardial infarction, Chronic heart failure with reduced ejection fraction (NYHA Class II), Chronic heart failure with reduced ejection fraction (NYHA Class III)

How Metodura ZNT works

Metodura ZNT is a beta-1-adrenergic receptor inhibitor specific to cardiac cells with negligible effect on beta-2 receptors. This inhibition decreases cardiac output by producing negative chronotropic and inotropic effects without presenting activity towards membrane stabilization nor intrinsic sympathomimetics.

Dosage

Metodura ZNT dosage

Oral-

Hypertension: Total daily dosage Metodura ZNT 100-400 mg to be given as a single or twice daily dose. The starting dose is 100 mg (two Metodura ZNT-50 tablets) per day. This may be increased by 100 mg per day at weekly intervals. lf full control is not achieved using a single daily dose, a b.i.d. regimen should be initiated. Combination therapy with a diuretic or other anti-hypertensive agent may also be considered.

Angina: Usually Metodura ZNT 50 mg (one Metodura ZNT-50 tablet) to 100 mg (two Metodura ZNT-50 tablets)twice or three times daily.

Cardiac arrhythmias: Metodura ZNT 50 mg (one Metodura ZNT-50 tablet) b.i.d or t.i.d should usually control the condition. It necessary the dose can be increased up to 300 mg per day in divided doses. Following the treatment of an acute arrhythmia with Metodura ZNT injection, continuationtherapy with Metodura ZNT tablets should be initiated 4-6 hours later. The initial oral dose should not exceed 50 mg t.i.d.

Hyperthyroidism: Metodura ZNT 50 mg (one Metodura ZNT-50 tablet) four times a day.The dose should bereduced as the euthyroid state is achieved.

Myocardial infarction: Orally, therapy should commence 15 minutes after the last injection with50 mg every 6 hours for 48 hours. Patients who fail to tolerate the full intravenous dose should begiven half the suggested oral dose. Maintenance – The usual maintenance dose is 200 mg dailygiven in divided doses. Elderly’ There are no special dosage requirements in otherwise healthyelderly patients. Signidcant hepatic dysfunction: A reduction in dosage may be necessary.

Injection-

Arrhythmias: By intravenous injection, up to 5 mg at a rate of 1-2 mg/minute, repeated after 5 minutes if necessary, total dose 10-15 mg.

In surgery: By slow intravenous injection 2-4 mg at induction or to control arrhythmias developing during anaesthesia; 2 mg doses may be repeated to a maximum of 10 mg.

Myocardial Infarction: Early intervention within 12 hours of infarction, by intravenous injection 5 mg every 2 minutes to a maximum of 15 mg, followed after 15 minutes by 50 mg by mouth every 6 hours for 48 hours; maintenance 200 mg daily in divided doses.

Impaired Renal Function: Dose adjustment is not needed in patients with impaired renal function.

Impaired Hepatic Function: Dose adjustment is not normally needed in patients suffering from liver cirrhosis because Metodura ZNT has low protein binding (5-10%). When there are signs of serious impairment of liver function (e.g. shunt-operated patients), a reduction in dose should be considered.

Elderly: Dose adjustment is not needed.

Side Effects

Bradycardia, bronchospasm, hypotension, headache, fatigue, sleep & gastro-intestinal disturbances, dizziness, vertigo, visual disturbances etc.

Toxicity

Oral administration of metoprolol to rats presents an LD50 in the range of 3090 to 4670 mg/kg. Cases of overdose have reported bradycardia, hypotension, bronchospasm, and cardiac failure. In the case of an overdose, gastric lavage is recommended followed by specific treatment according to symptoms.

Metodura ZNT is not reported to be carcinogenic nor mutagenic nor to impair fertility. The only event registered is the increase of macrophages in pulmonary alveoli and slight biliary hyperplasia. When metoprolol was given for long periods of time on the highest dose, there was evidence of small benign lung tumors.

Precaution

The second or third dose should not be given if the heart rate is <40 beats/minute, the P-R interval is > 0.26 seconds and the systolic blood pressure is <90 mmHg or if there is any aggravation of dyspnoea or cold sweating. Intravenous administration of calcium antagonists of the Verapamil-type should not be given to patients treated with beta-blockers. When treating patients with suspected or definite myocardial infarction, the haemodynamic status of the patient should be carefully monitored after each of the three 5 mg intravenous doses. Use in Pregnancy: As with most medicines, Metodura ZNT should not be given during pregnancy and lactation unless its use is considered essential. As with all antihypertensive agents, beta-blockers may cause side effects (e.g. bradycardia) in the foetus and in the newborn and breast-fed infant. Use in Lactation: The amount of Metodura ZNT ingested via breast-milk seems to be negligible as regards beta-blocking effect in the infant if the mother is treated with Metodura ZNT doses within the normal therapeutic range.

Interaction

Plasma level of Metodura ZNT may be raised by co-administration of compounds metabolished by CYP2D6 e.g. Antiarrhythmics, antihistamines, H2 receptor antagonists, antidepressants, antipsychotics and COX-2 inhibitors. The plasma conc. of Metodura ZNT is lowered by Rifampicin.

Food Interaction

• Avoid alcohol.
• Avoid natural licorice.
• Take with food.

[Moderate] ADJUST DOSING INTERVAL: The bioavailability of metoprolol may be enhanced by food.

MANAGEMENT: Patients may be instructed to take metoprolol at the same time each day, preferably with or immediately following meals.

Metodura ZNT Alcohol interaction

[Moderate]

Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation.

Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

Caution and close monitoring for development of hypotension is advised during coadministration of these agents.

Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs.

Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

Metodura ZNT Cholesterol interaction

[Moderate] Beta-adrenergic receptor blocking agents (aka beta-blockers) may alter serum lipid profiles.

Increases in serum VLDL and LDL cholesterol and triglycerides, as well as decreases in HDL cholesterol, have been reported with some beta-blockers.

Patients with preexisting hyperlipidemia may require closer monitoring during beta-blocker therapy, and adjustments made accordingly in their lipid-lowering regimen.

Metodura ZNT multivitamins interaction

[Moderate] ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers.

The exact mechanism of interaction is unknown.

In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively.

The elimination half-life increased by 44%.

Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone.

However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments.

The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours.

Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.

Metodura ZNT Drug Interaction

Moderate: duloxetine, insulin glargine, furosemide, alprazolamMinor: aspirin, aspirin, levothyroxineUnknown: ubiquinone, rosuvastatin, apixaban, omega-3 polyunsaturated fatty acids, atorvastatin, pregabalin, esomeprazole, clopidogrel, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, rivaroxaban

Metodura ZNT Disease Interaction

Major: bradyarrhythmia/AV block, cardiogenic shock/hypotension, CHF, diabetes, hemodialysis, hypersensitivity, ischemic heart disease, PVD, liver diseaseModerate: cerebrovascular insufficiency, glaucoma, hyperlipidemia, hyperthyroidism, hyperthyroidism PKs, myasthenia gravis, pheochromocytoma, psoriasis, tachycardia, asthma/COPD

Volume of Distribution

The reported volume of distribution of metoprolol is 4.2 L/kg. Due to the characteristics of metoprolol, this molecule is able to cross the blood-brain barrier and even 78% of the administered drug can be found in cerebrospinal fluid.

Elimination Route

When metoprolol is administered orally, it is almost completely absorbed in the gastrointestinal tract. The maximum serum concentration is achieved 20 min after intravenous administration and 1-2 hours after oral administration. The bioavailability of metoprolol is of 100% when administered intravenously and when administered orally it presents about 50% for the tartrate derivative and 40% for the succinate derivative.

The absorption of metoprolol in the form of the tartrate derivative is increased by the concomitant administration of food.

Half Life

The immediate release formulations of metoprolol present a half-life of about 3-7 hours.

Clearance

The reported clearance rate on patients with normal kidney function is 0.8 L/min. In cirrhotic patients, the clearance rate changes to 0.61 L/min.

Elimination Route

Metodura ZNT is mainly excreted via the kidneys. From the eliminated dose, less than 5% is recovered unchanged.

Pregnancy & Breastfeeding use

Metodura ZNT should not be used in pregnancy or lactating mothers unless the physician considers that the benefit outweighs the possible hazard to the fetus or infant.

Contraindication

2nd or 3rd degree AV block, sick sinus syndrome, hypotension, decompensated heart failure, sinus bradycardia, severe peripheral arterial circulatory disorders, cardiogenic shock, severe asthma and bronchospasm, untreated phaeochromocytoma, Prinzmetal's angina, metabolic acidosis.

Special Warning

Renal Impairment: No dosage adjustment needed.

Hepatic Impairment: Reduce dose.

Acute Overdose

Poisoning due to an overdose of metoprolol may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness, coma, nausea, vomiting, cyanosis, hypoglycaemia and, occasionally, hyperkalaemia. The first manifestations usually appear 20 minutes to 2 hours after drug ingestion. Treatment: Treatment should include close monitoring of cardiovascular, respiratory and renal function, and blood glucose and electrolytes. Further absorption may be prevented by induction of vomiting, gastric lavage or administration of activated-charcoal if ingestion is recent. Cardiovascular complications should be treated symptomatically, which may require the use of sympathomimetic agents (e.g. noradrenaline, metaramionl), atropine or inotropic agents (e.g. dopamine, dobutamine). Temporary pacing may be required for AV block. Glucagon can reverse the effects of excessive B-blockade, given in a dose of 1-10 mg intravenously. Intravenous B2-stimulants e.g. terbutaline may be required to relieve bronchospasm. Metodura ZNT cannot be effectively removed by haemodialysis.

Storage Condition

Store in a cool, dry place protected from light. Keep out of reach of children.

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