Enzopril A

Uses

Patients with mild to moderate hypertension (alone or in combination with other antihypertensives).

The treatment of chronic stable and vasospastic angina.

Raynaud\'s disease.

Hypertension: Lisinopril is used for the treatment of hypertension in adult patients and pediatric patients 6 years of age and older to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.Lisinopril may be administered alone or with other antihypertensive agents.

Heart Failure: Lisinopril is used to reduce signs and symptoms of heart failure in patients who are not responding adequately to diuretics and digitalis.

Acute Myocardial Infarction: Lisinopril is used for the reduction of mortality in treatment of hemodynamically stable patients within 24 hours of acute myocardial infarction. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers

Enzopril A 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 AnginaAcute Myocardial Infarction (AMI), Cardiovascular Events, Congestive Heart Failure (CHF), Diabetic Nephropathy, High Blood Pressure (Hypertension), Migraine

How Enzopril A 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 .

Angiotensin II constricts coronary blood vessels and is positively inotropic, which under normal circumstances, would increase vascular resistance and oxygen consumption. This action can eventually lead to myocyte hypertrophy and vascular smooth muscle cell proliferation.

Lisinopril is an angiotensin converting enzyme inhibitor (ACEI), preventing the conversion of angiotensin I to angiotensin II. This action prevents myocyte hypertrophy and vascular smooth muscle cell proliferation seen in untreated patients. Increased levels of bradykinin also exhibit vasodilating effects for patients taking ACEIs. Lisinopril also inhibits renin's conversion of angiotensin to angiotensin I.

Dosage

Enzopril A dosage

For treatment of both hypertension and angina pectoris, the usual initial dose is 5 mg once daily. If the desired therapeutic effect cannot be achieved within 2-4 weeks, the dose may be increased to a maximum dose of 10 mg once daily. Amlodipine 10 mg once daily provides symptomatic improvement in patients with Raynaud's disease.

Use in children: Use of Amlodipine in children (under 12 years of age) is not recommended.

Oral (Adult)-

Hypertension:

Initially, 10 mg/day, 1st dose given preferably at bedtime to avoid precipitous fall in BP. Patient with renovascular HTN, volume depletion, severe HTN: Initially, 2.5-5 mg once daily. Patient on diuretic: Initially, 5 mg once daily. Maintenance: 20 mg once daily, up to 80 mg/day may be given if needed.

Diabetic nephropathy: Hypertensive type 2 diabetics with microalbuminuria: 10 mg once daily, may increase to 20 mg once daily to achieve a sitting diastolic BP

Heart failure: As adjunct: Initially, 2.5 or 5 mg/day, increased by increments of ≤10 mg at intervals of at least 2 wk to max maintenance dose of 40 mg/day.

Post-myocardial infarction: Initially, 5 mg once daily for 2 days started within 24 hr of the onset of symptoms. Increase to 10 mg once daily. Patients with low systolic BP: Initially, 2.5 mg once daily.

Oral (Child)-

Hypertension: ≥6 yr Initially, 0.07 mg/kg, up to 5 mg once daily.

Side Effects

Amlodipine is generally well tolerated. The most commonly observed side effects are headache, peripheral oedema, palpitations, flushing, dizziness, nausea, abdominal pain.

Headache, fatigue, persistent and non-productive cough, chest and abdominal pain, dizziness, nausea, vomiting, diarrhoea, upper resp tract infection, asthenia, rash, orthostatic effects, hypotension, renal dysfunction, hyperkalaemia, intestinal angioedema; increased BUN and serum creatinine levels.

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 oral and subcutaneous LD₅₀ in rats is >8500mg/kg and in mice is >9100mg/kg. The oral LDLO in women is 1200µg/kg/16D and in men is 43mg/kg/43W.

Patients experiencing an overdose of lisinopril may present with hypotension. Patients should be treated with intravenous saline to restore blood pressure. Lisinopril can be removed from the blood by hemodialysis due to it not being protein bound.

Precaution

Hypotension: Since the vasodilUse in renal failure

Although Amlodipine is excreted primarily via kidney, mild renal impairment does not appear to have an effect on the plasma concentrations. Severe renal impairment may however require a dosage reduction. Amlodipine is not dialyzable.

Use in patients with impaired hepatic function

Amlodipine half-life is prolonged in patient with impaired hepatic function. Amlodipine should therefore be administered at lower (5mg) initial dose in these patients.

Use in heart failure

An increased number of pulmonary oedema has been reported.atation induced by Amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration of Amlodipine. Nonetheless, caution should be exercised when administering the drug with any other peripheral vasodilator particularly in patients with severe aortic stenosis.

Cardiac failure: Patients with heart failure should be treated with caution. Calcium channel blockers, including Amlodipine, should be usedwith caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Beta blocker withdrawal: Amlodipine gives no protection against the danger of abrupt beta blocker withdrawal; any such withdrawal should be gradualreduction of the dose of beta blocker.

Hepatic failure: The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

Bilateral renal artery stenosis or a single kidney with unilateral renal artery stenosis. Patients with collagen vascular disease, acute MI at risk of further haemodynamic deterioration, angioedema unrelated to ACE inhibitor therapy, aortic stenosis and hypertrophic cardiomyopathy. Increased risk of angioedema in black patients. Renal impairment. Lactation. Childn <6 yr.

Interaction

Use of Amlodipine together with thiazide diuretics or angiotensin-converting-enzyme inhibitors in the treatment of hypertension is additive. There are no hazardous interaction of Amlodipine with Digoxin, Cimetidine, Warfarin and food.

May enhance hypotensive effect with diuretics. May increase risk of renal function deterioration and decrease antihypertensive effect with NSAIDs. May increase serum levels and toxicity of lithium. Increased risk of hyperkalaemia with K-sparing diuretics and K supplements. May increase nitritoid reactions of gold Na thiomalate.

Volume of Distribution

21 L/kg , .

The apparent volume of distribution of lisinopril is 124L.

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 .

Lisinopril is 6-60% orally bioavailable with an average of 25% bioavailability. Lisinopril reaches a C_max of 58ng/mL with a T_max of 6-8h. Lisinopril's absorption is not affected by food.

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 .

Lisinopril has an effective half life of accumulation of 12.6h and a terminal half life of 46.7h.

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 .

A 30kg child has a typical clearance of 10L/h, which increases with renal function. The mean renal clearance of lisinopril in healthy adult males is 121mL/min.

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 , .

Lisinopril is entirely eliminated exclusively in the urine.

Pregnancy & Breastfeeding use

Pregnancy: Safety in pregnancy has not been established.

Lactation: It is not known whether Amlodipine is excreted in breast milk. It is advised to stop breastfeeding during treatment with Amlodipine.

Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Amlodipine is contraindicated in patients with-

• Hypersensitivity to amlodipine, dihydropyridine derivatives or any of the excipients
• Shock (including cardiogenic shock)
• Obstruction of the outflow-tract of the left ventricle (e.g. high grade aortic stenosis)
• Unstable angina
• Hemodynamically unstable heart failure after acute myocardial infarction (during the first 28 days)
• Severe hypotension

History of angioedema related to previous ACE inhibitor treatment, hereditary or idiopathic angioedema. Concomitant use with aliskiren in patients with diabetes or renal impairment. Pregnancy. Children with GFR <30 mL/min/1.73 m2.

Special Warning

Children with hypertension from 6 years to 17 years of age: 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients.

Children under 6 years old: The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Elderly: Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

Renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Hepatic impairment: Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautions and should start at the lower end of the dosing range. The pharmacokinetics of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose (2.5 mg once daily) and titrated slowly in patients with severe hepatic impairment.

Adult:

• CrCl 10-30 ml/min: Initially, 2.5-5 mg once daily.
• CrCl 31-80 ml/min: Initially 5-10 mg once daily. Dose can be adjusted up to max 40 mg once daily based on patient's response.

Child: Do not give if GFR <30 mL/min/1.73 m2.

Acute Overdose

There is no well documented experience with Amlodipine overdosage. In case of clinically significant hypotension due to Amlodipine over dosage, calls for active cardiovascular support including monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output. Since Amlodipine is highly protein-bound, dialysis is unlikely to be of benefit.

Symptoms: Hypotension, tachycardia, circulatory shock, palpitations, bradycardia, hyperventilation, renal failure, electrolyte disturbances, anxiety, dizziness and cough.

Management: Normal saline IV infusion may be used. Perform haemodialysis, emesis, gastric lavage, admin of absorbents and Na sulfate if recently taken. Consider admin of angiotensin II infusion and/or IV catecholamines if available.

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.

Store at below 25° C.

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