Met Xl Nt

Uses

Isosorbide mononitrate tablets are used for-

• The prevention of angina pectoris due to coronary artery disease. The onset of action of oral isosorbide mononitrate is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.
• Long-term treatment of blood-flow disorders of the coronary vessels (coronary heart disease)
• Long-term treatment and prophylaxis of angina pectoris (chest pain due to coronary blood-flow disorders of the coronary vessels).
• Treatment of severe myocardial insufficiency (chronic heart failure)

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

Met Xl Nt is also used to associated treatment for these conditions: Angina PectorisAngina 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 Met Xl Nt works

Isosorbide mononitrate acts as a prodrug for nitric oxide (NO), which is a potent vasodilator gas that is released when the drug is metabolized. NO activates soluble guanylyl cyclase in vascular endothelial cells, which increases the intracellular concentrations of cyclic GMP (cGMP). cGMP activates cGMP-dependent protein kinases, such as protein kinase G and I, which activates the downstream intracellular cascades. The downstream cascade results in reduced intracellular concentrations of calcium, caused by processes including inhibition of IP₃-mediated pathway, phosphorylation of big calcium-activated potassium channel leading to cell hyperpolarization and reduced calcium influx, and increased calcium efflux via the Ca2+-ATPase-pump. Reduced intracellular calcium concentrations lead to the dephosphorylation of myosin light chains and the relaxation of smooth muscle cells.

Metoprolol 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

Met Xl Nt dosage

The recommendedregimenof Isosorbide Mononitrate tablets is 20 mg (one tablet) twice daily, with the two doses given 7 hours apart. For most patients, this can be accomplished by taking the first dose on awakening and the second dose 7 hours later. Dosage adjustments are not necessary for elderly patients or patients with alteredrenalorhepaticfunction.

Multiple studies oforganicnitrates have shown that maintenance of continuous 24-hourplasmalevels results inrefractorytolerance. The dosing regimen for Isosorbide Mononitrate tablets provides a daily nitrate-free interval to avoid the development of this tolerance. Well-controlled studies have shown that tolerance to Isosorbide Mononitrate tablets is avoided when using the twice-daily regimen in which the two doses are given 7 hours apart. This regimen has been shown to have antianginal efficacy beginning 1 hour after the first dose and lasting at least 5 hours after the second dose. The duration (if any) of antianginal activity beyond 12 hours has not been studied; large controlled studies with other nitrates suggest that no dosing regimen should be expected to provide more than about 12 hours of continuous antianginal efficacy per day.

Inclinical trials, Isosorbide Mononitrate tablets have been administered in a variety of regimens. Single doses less than 20 mg have not been adequately studied, while single doses greater than 20 mg have demonstrated no greater efficacy than doses of 20 mg.

Oral-

Hypertension: Total daily dosage Metoprolol 100-400 mg to be given as a single or twice daily dose. The starting dose is 100 mg (two Metoprolol-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 Metoprolol 50 mg (one Metoprolol-50 tablet) to 100 mg (two Metoprolol-50 tablets)twice or three times daily.

Cardiac arrhythmias: Metoprolol 50 mg (one Metoprolol-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 Metoprolol injection, continuationtherapy with Metoprolol tablets should be initiated 4-6 hours later. The initial oral dose should not exceed 50 mg t.i.d.

Hyperthyroidism: Metoprolol 50 mg (one Metoprolol-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 Metoprolol 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

Hypotension, tachycardia, flushing, headache, dizziness, palpitation, syncope, confusion. Nausea, vomiting, abdominal pain. Restlessness, weakness and vertigo. Dry mouth, chest pain, back pain, oedema, fatigue, abdominal pain, constipation, diarrhoea, dyspepsia and flatulence.

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

Toxicity

The oral LD₅₀ is 2010 mg/kg in rats and 1771 mg/kg in mice.

The symptoms of overdose from isosorbide mononitrate is associated with vasodilatation, venous pooling, reduced cardiac output, and hypotension. These symptoms can be accompanied by several manifestations, including increased intracranial pressure (possibly along with persistent throbbing headache, confusion, and moderate fever), vertigo, palpitations, visual disturbances, nausea and vomiting (possibly along with colic and bloody diarrhea), syncope (especially in the upright posture), air hunger and dyspnea (later followed by reduced ventilatory effort), diaphoresis (with flushed or cold and clammy skin), heart blocks and bradycardia, paralysis, coma, seizures, and death.

There is limited clinical information on the management of isosorbide mononitrate overdose; it is advised that venodilatation and arterial hypovolemia from overdose are responded with therapy aimed to increase in central fluid volume. However, this method may be potentially hazardous in patients with renal disease or congestive heart failure: invasive monitoring may be required in these patients. The patient's legs should be passively elevated, and intravenous infusion of normal saline or similar fluid is recommended. Isosorbide mononitrate was shown to be significantly removed from the systemic circulation via hemodialysis. The use of epinephrine or other arterial vasoconstrictors is not recommended.

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.

Metoprolol 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

Severe renal or severe hepatic impairment, hypothyroidism, malnutrition, or hypothermia. Caution in patients who are already hypotensive. May aggravate angina caused by hypertrophic cardiomyopathy. Tolerance may develop after long-term treatment. Lactation.

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, Metoprolol 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 Metoprolol ingested via breast-milk seems to be negligible as regards beta-blocking effect in the infant if the mother is treated with Metoprolol doses within the normal therapeutic range.

Interaction

Hypotensive effects may be increased when used with alcohol or vasodilators. Concurrent use with calcium channel blockers may lead to marked orthostatic hypotension.

Plasma level of Metoprolol 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 Metoprolol is lowered by Rifampicin.

Volume of Distribution

The volume of distribution is approximately 0.6 L/kg, which is approximately the volume of total body water.

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

Upon oral administration, isosorbide mononitrate is rapidly and completely absorbed from the gastrointestinal tract. Isosorbide mononitrate has a dose-linear kinetics and the absolute bioavailability is nearly 100%. The Cmax is reached within 30 to 60 minutes following administration.

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 elimination half-life of isosorbide mononitrate is about 5 hours. The elimination half-life of its metabolites, isosorbide and 2-glucuronide of mononitrate, are 8 hours and 6 hours, respectively.

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

Clearance

The total body clearance is 115-120 mL/min.

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

In a human radio-labelled drug study, about 93% of the total dose was excreted in the urine within 48 hours. Following oral administration of 20 mg, only 2% of isosorbide mononitrate was excreted unchanged in the urine within 24 hours. Among the excreted dose, nearly half of the dose was found de-nitrated in urine as isosorbide and sorbitol: approximately 30% is excreted as isosorbide and about 17% is the 2-glucuronide of mononitrate. These metabolites were not vasoactive or pharmacologically active. Renal excretion was complete after 5 days, and fecal excretion accounted for only 1% of drug elimination.

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

Pregnancy & Breastfeeding use

There are no adequate and controlled studies to date with Isosorbide-5-mononitrate in pregnant women, and the drug should be used during pregnancy only when the potential benefit justified possible risks to the fetus. Execration of Isosorbide-5-mononitrate into human milk is unknown, so precaution should be taken when it is administered to a nursing mother.

Metoprolol 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

It is contraindicated in patients who have shown hypersensitivity or idiosyncratic reactions to other nitrates or nitrites.

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

Symptoms : Most common symptoms are hypotension, throbbing headache, tachycardia, and flushing. Methemoglobinemia may occur with massive doses.

Treatment: Treatment consists of placing patients in recumbent position and administering fluids; alpha-adrenergic vasopressors may be required. Methemoglobinemia should be treated with methyline blue at a dose of 1-2 mg/kg IV slowly.

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. Metoprolol cannot be effectively removed by haemodialysis.

Storage Condition

Store at 20-25° C.

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

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