Amlodipine And Olmesartan

Uses

Amlodipine & Olmesartan is used for the treatment of hypertension, alone or with other antihypertensive agents. This may also be used as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals.

Amlodipine And Olmesartan is also used to associated treatment for these conditions: Anginal Pain, Cardiovascular Events, Chronic Stable Angina Pectoris, Coronary Artery Disease (CAD), High Blood Pressure (Hypertension), Homozygous Familial Hypercholesterolemia, Hypertension,Essential, Mixed Dyslipidemias, Primary Hypercholesterolemia, Vasospastic AnginaDiabetic Nephropathy, High Blood Pressure (Hypertension), Severe Hypertension, Moderate Hypertension

How Amlodipine And Olmesartan works

Mechanism of action on blood pressure

Amlodipine is considered a peripheral arterial vasodilator that exerts its action directly on vascular smooth muscle to lead to a reduction in peripheral vascular resistance, causing a decrease in blood pressure. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the influx of calcium ions into both vascular smooth muscle and cardiac muscle. Experimental studies imply that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites, located on cell membranes. The contraction of cardiac muscle and vascular smooth muscle are dependent on the movement of extracellular calcium ions into these cells by specific ion channels. Amlodipine blocks calcium ion influx across cell membranes with selectivity. A stronger effect of amlodipine is exerted on vascular smooth muscle cells than on cardiac muscle cells . Direct actions of amlodipine on vascular smooth muscle result in reduced blood pressure .

Mechanism of action in angina

The exact mechanism by which amlodipine relieves the symptoms of angina have not been fully elucidated to this date, however, the mechanism of action is likely twofold:

Amlodipine has a dilating effect on peripheral arterioles, reducing the total peripheral resistance (afterload) against which the cardiac muscle functions. Since the heart rate remains stable during amlodipine administration, the reduced work of the heart reduces both myocardial energy use and oxygen requirements .

Dilatation of the main coronary arteries and coronary arterioles, both in healthy and ischemic areas, is another possible mechanism of amlodipine reduction of blood pressure. The dilatation causes an increase in myocardial oxygen delivery in patients experiencing coronary artery spasm (Prinzmetal's or variant angina) and reduces coronary vasoconstriction caused by smoking .

Olmesartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which also includes telmisartan, candesartan, losartan, valsartan, and irbesartan. ARBs selectively bind to angiotensin receptor 1 (AT1) and prevent the protein angiotensin II from binding and exerting its hypertensive effects. As the principal pressor agent of the renin-angiotensin system, Angiotensin II causes vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis. Overall, olmesartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium.

Olmesartan also effects on the renin-angiotensin aldosterone system (RAAS) plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS, which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and preventing ventricular hypertrophy and remodelling.

Dosage

Amlodipine And Olmesartan dosage

Initial Therapy: The usual starting dose of Amlodipine & Olmesartanis one tablet (5/20 mg) once daily. Thedosage can be increased after 1 to 2 weeks of therapy to a maximum dose is two tablets (10/40 mg) once daily as needed to control bloodpressure. This may be taken with or without food and may beadministered with other antihypertensive agents.Initial therapy with this combination product is not recommended in patients ≥75 years old or with hepatic impairment.

Replacement Therapy: Amlodipine & Olmesartanmay be substituted for its individually titrated components. Whensubstituting for individual components, the dose of one or both of the components can be increased if blood pressure control has not been satisfactory.

Add-on Therapy: Amlodipine & Olmesartanmay be used to provide additional blood pressure lowering forpatients not adequately controlled with Amlodipine (or another dihydropyridinecalcium channel blocker) alone or with Olmesartan Medoxomil (or another angiotensin II receptor blocker) alone.

Side Effects

The reported adverse reactions were generally mild and seldom led to discontinuation of treatment. The most common side effects include edema, dizziness, flushing, palpitation. Other side effects may include vomiting, diarrhoea, rhabdomyolysis, alopecia, pruritus, urticaria etc.

Toxicity

Acute oral toxicity (LD50): 37 mg/kg (mouse) .

Overdose

An overdose of amlodipine could result in a high degree of peripheral vasodilatation with a possibility of reflex tachycardia. Significant and prolonged hypotension leading to shock and fatal outcomes have been reported .

Carcinogenesis, mutagenesis, impairment of fertility

Rats and mice treated with amlodipine maleate in the diet on a long-term basis for up to 2 years demonstrated no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was comparable to the maximum recommended human dose of 10 mg amlodipine per day. For the rat, the highest dose was measured to be about twice the maximum recommended human dose .

Mutagenicity studies using amlodipine maleate showed no drug-related gene or chromosomal effects .

There was no impact on the fertility of rats given oral amlodipine maleate (males for 64 days and females for 14 days before mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose) .

Use in pregnancy

The safety of amlodipine in human pregnancy or lactation has not been proven. Amlodipine is therefore considered a pregnancy category C drug . Use amlodipine only if the potential benefit justifies the potential risk .

Use in nursing

Discontinue when administering amlodipine .

The reported LD50 of olmesartan in dogs was reported to be greater of 1500 mg/kg. Overdose is expressed as hypotension, tachycardia, and bradycardia when there is parasympathetic stimulation. In case of overdose, supportive treatment is recommended.

Olmesartan was shown to be safe on carcinogenic and fertility studies. However, in in vitro mutagenic studies showed a potential to induce chromosomal aberrations in cells and it tested positive for thymidine kinase mutations in the mouse lymphoma assay.

Precaution

Fetal/Neonatal Morbidity and Mortality: When pregnancy is detected, this combination should be discontinued as soon as possible.

Hypotension in Volume or Salt Depleted Patients: Symptomatic hypotension may occur after initiation of treatment.

Vasodilatation: Caution should be exercised when administering the drug, particularly in patients with severe aortic stenosis.

Patients with Severe Obstructive Coronary Artery Disease: Patients may develop increased frequency, duration, or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase.

Patients with Congestive Heart Failure: Calcium channel blockers should be used with caution in patients with heart failure.

Patients with Impaired Renal Function: Caution should be exercised when administering the drug to patients with renal impairment.

Patients with Hepatic Impairment: Caution should be exercised when administering the drug to patients with severe hepatic impairment.

Interaction

The pharmacokinetics of Amlodipine and Olmesartan Medoxomil are not altered when the drugs are co administered. No drug interaction studies have been conducted with Amlodipine and Olmesartan combination tablet and other drugs, although studies have been conducted with the individual Amlodipine and Olmesartan Medoxomil components and no significant drug interactions have been observed.

Volume of Distribution

21 L/kg , .

17 L[L5566]

Elimination Route

Amlodipine absorbed slowly and almost completely from the gastrointestinal tract. Peak plasma concentrations are achieved 6-12 hours after oral administration. The estimated bioavailability of amlodipine is 64-90%. Steady-state plasma amlodipine levels are achieved after 7-8 days of consecutive daily dosing. Absorption is not affected by food .

When taken orally, the prodrug olmesartan medoxomil is rapidly absorbed in the gastrointestinal tract and metabolized to olmesartan. The esterification with medoxomil was created with the intention of increasing olmesartan bioavailability from 4.5% to 28.6%.

Oral administration of 10-160 mg of olmesartan has been shown to reach peak plasma concentration of 0.22-2.1 mg/L after 1-3 hours with an AUC of 1.6-19.9mgh/L. The pharmacokinetic profile of olmesartan has been observed to be nearly linear and dose-dependent under the therapeutic range. The steady-state level of olmesartan is achieved after once a day dosing during 3 to 5 days.[L5566]

Half Life

The terminal elimination half-life of about 30–50 hours .

Plasma elimination half-life is 56 hours in patients with impaired hepatic function, titrate slowly when administering this drug to patients with severe hepatic impairment .

The mean plasma olmesartan half-life is reported to be from 10-15 hours after multiple oral administration.

Clearance

Total body clearance (CL) has been calculated as 7 ± 1.3 ml/min/kg (0.42 ± 0.078 L/ h/kg) in healthy volunteers , .

Elderly patients show a reduced clearance of amlodipine with an AUC (area under the curve) increase of about 40–60%, and a lower initial dose may be required .

Total plasma clearance is 1.3 L/h and the renal clearance is 0.6 L/h.[L5566]

Elimination Route

Elimination from the plasma occurs in a biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7-8 days of consecutive daily dosing . Amlodipine is 10% excreted as unchanged drug in the urine. Amlodipine can be initiated at normal doses in patients diagnosed with renal failure , .

The main elimination route of olmesartan is in the unchanged form through the feces. From the systemically bioavailable dose, about 10-16% is eliminated in the urine.

Pregnancy & Breastfeeding use

Pregnancy: When pregnancy is detected, discontinue this combination product as soon as possible. When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus.

Nursing Mothers: Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Hypersensitivity to any of the component of this combination product.

Special Warning

The safety and effectiveness in pediatric patients have not been established.

Acute Overdose

There is no experience of overdose with Amlodipine & Olmesartan combination. The most likely effects of olmesartan medoxomil overdosage are hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurred.

Amlodipine overdosage can be expected to lead to excessive peripheral vasodilatation with marked hypotension and possibly a reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome has been reported.

Storage Condition

Keep out of the reach of children. Store below 30°C. Keep in the original package in a cool & dry place in order to protect from light and moisture.

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