Metozest R

Uses

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.

Ramiprilis used for the following cases:

• Mild to severe hypertension
• Congestive Heart failure.
• To reduce the risk of stroke, myocardial infarction and death from cardiovascular events in patients with a history of cardiovascular disease.
• Proteinuric non-diabetic nephropathy.

Metozest R 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)Cardiovascular Events, Diabetic Nephropathy, Heart Failure, Heart Failure With Reduced Ejection Fraction (HFrEF), High Blood Pressure (Hypertension), Myocardial Infarction, Nondiabetic proteinuric chronic kidney disease, Stroke, High risk cardiovascular event

How Metozest R works

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.

Ramipril inhibits the RAAS system by binding to and inhibiting ACE thereby preventing the conversion of angiotensin I to angiotensin II. As plasma levels of angiotensin II fall, less activation of the G-protein coupled receptors angiotensin receptor I (AT₁R) and angiotensin receptor II (AT₂R) occurs.

AT₁R mediates vasoconstriction, inflammation, fibrosis, and oxidative stress through a variety of signaling pathways. These include G_q coupling to the inositol triphosphate pathway, activation of phospholipases C, A₂, and D which contribute to eicosanoid production, activation of Ca^{2+ These counteracting effects are shared by the Mas receptor which is activated by Ang(1-7), a subtype of angiotensin produced by plasma esterases from AngI or by ACE2 from AngII produced through a secondary pathway by tonin and cathepsin G. Ang(1-7) also activates AT₂R although the bulk of its effect is mediated by MasR.}

ACE is also responsible for the breakdown of bradykinin. The resulting buildup of bradykinin due to ACE inhibition is thought to mediate the characteristic dry-cough as a side effect of ACE inhibitor medications.

Dosage

Metozest R dosage

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.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25 - 2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5 - 20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Side Effects

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

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

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.

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.

Symptoms of overdose may include excessive peripheral vasodilation (with marked hypotension and shock), bradycardia, electrolyte disturbances, and renal failure. Cases of ACE inhibitor induced hepatotoxicity have been reported in humans and presented as acute jaundice and elevated liver enzymes. Removal of the ACE inhbitor resulted in a decline in liver enzymes and re-challenge produced a subsequent increase.

There were no observed tumerogenic effects at chronic doses up to 500mg/kg/day to rats for 24 months or at doses up to 1000mg/kg/day to mice for 18 months. For both species doses were administered by gavage and equivalent to 200 time the maximum recommended human exposure based on body surface area.

No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites of ramipril also produced negative results in the Ames test.

No effects on fertility were seen in rats at doses up to 500mg/kg/day. No teratogenicity was observed in rats and cynomolgus monkeys at doses 400 times the maximum recommended human exposure nor in rabbites at 2 times the maximum recommended human exposure.

LD₅₀ 10 g/kg (rat). LD₅₀ 10.5 g/kg (mouse). LD₅₀ 1 g/kg (dog).

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, 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.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Interaction

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.

With Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril.

With Potassium Supplements and Potassium-sparing Diuretics: Ramipril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia.

Other: Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate). The co-administration of ramipril and warfarin did not adversely affect the anticoagulant effects of the latter drug.

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.

The extent of absorption is at least 50-60%.. Food decreases the rate of absorption from the GI tract without affecting the extent of absorption. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when oral administration was compared to intravenous administration. The serum concentration of ramiprilat was unchanged when capsules were opened and the contents dissolved in water, dissolved in apple juice, or suspended in apple sauce.

Half Life

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

Plasma concentrations of ramiprilat decline in a triphasic manner. Initial rapid decline represents distribution into tissues and has a half life of 2-4 hours. The half life of the apparent elimination phase is 9-18 hours, which is thought to represent clearance of free drug. The half-life of the terminal elimination phase is > 50 hours and thought to represent clearance of drug bound to ACE due to its slow dissociation. The half life of ramiprilat after multiple daily doses (MDDs) is dose-dependent, ranging from 13-17 hours with 5-10 mg MDDs to 27-36 hours for 2.5 mg MDDs.

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.

The renal clearance of ramipril and ramiprilat was reported to be 7.2 and 77.4 mL/min/1.73m². The mean renal clearance of ramipril and ramiprilat is reported to be 10.7 and 126.8 mL/min in healthy elderly patients with normal renal function, additionally the Cmax of ramiprilat is approximately 20% higher in this population. While the pharmacokinetics of ramipril appear unaffected by reduced renal function, the plasma concentration and half-life of ramiprilat are increased. In patient's with hepatic failure the concentration of ramipril is initially increased while the tmax of ramiprilat is prolonged due to a reduced ability to metabolize the drug. However, steady state concentrations of ramiprilat are the same in hepatic failure as in healthy patients.

Elimination Route

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

Following oral administration, about 60% of the dose is eliminated in the urine as unchanged ramipril (6

Pregnancy & Breastfeeding use

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.

If pregnancy is detected, ramipril should be discontinued as early as possible unless continued use is considered life saving. Ramipril should not be used during lactation.

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.

It is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with a ACE inhibitor.

Special Warning

Renal Impairment: No dosage adjustment needed.

Hepatic Impairment: Reduce dose.

Dosage in renal impairment: For the patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily. For the patients with heart failure and renal impairment, the recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Use in children: No information is yet available on the use of Ramipril in children.

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. Metoprolol cannot be effectively removed by haemodialysis.

Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension. Because the hypotensive effect of Ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat Ramipril overdosage by infusion of normal saline solution.

Storage Condition

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

Store at cool & dry place, protect from light and moisture.

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