Mirapril

Uses

Miraprilis 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.

Mirapril is also used to associated treatment for these conditions: 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 Mirapril works

Mirapril 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

Mirapril dosage

Dosage of Mirapril 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 Mirapril 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 Mirapril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Mirapril 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

Mirapril 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

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

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

Interaction

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: Mirapril 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.

Food Interaction

• Avoid potassium-containing products. Potassium products increase the risk of hyperkalemia.
• Take with or without food. The absorption is unaffected by food.

[Moderate] GENERALLY AVOID: Moderate-to-high dietary intake of potassium can cause hyperkalemia in some patients who are using angiotensin converting enzyme (ACE) inhibitors.

In some cases, affected patients were using a potassium-rich salt substitute.

ACE inhibitors can promote hyperkalemia through inhibition of the renin-aldosterone-angiotensin (RAA) system.

MANAGEMENT: It is recommended that patients who are taking ACE inhibitors be advised to avoid moderately high or high potassium dietary intake.

Particular attention should be paid to the potassium content of salt substitutes.

Mirapril Drug Interaction

Moderate: aspirin, aspirin, insulin glargine, furosemide, pregabalinUnknown: ubiquinone, rosuvastatin, duloxetine, apixaban, omega-3 polyunsaturated fatty acids, atorvastatin, metoprolol, metoprolol, esomeprazole, acetaminophen, clopidogrel, levothyroxine, cyanocobalamin, ascorbic acid, cholecalciferol

Mirapril Disease Interaction

Major: angioedema, bone marrow suppression, CHF, hemodialysis, hyperkalemia, hypotensionModerate: liver disease, renal dysfunction

Elimination Route

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

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 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

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

Pregnancy & Breastfeeding use

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

Contraindication

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

Dosage in renal impairment: For the patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg Mirapril 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 Mirapril in children.

Acute Overdose

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

Storage Condition

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

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