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Amlodipine is a dihydropyridine calcium-channel blocker. It is a peripheral and coronary vasodilator, but, unlike the calcium-channel blockers verapamil or diltiazem, has little or no cardiac conduction and negative inotropic activity is rarely seen at therapeutic doses.

Administration of amlodipine results primarily in vasodilation, with reduced peripheral resistance, blood pressure, and afterload, increased coronary blood flow, and a reflex increase in heart rate. This, in turn, results in an increase in myocardial oxygen supply and cardiac output.

Uses of amlodipine

It is used in the management of

Hypertension,
Coronary Artery Disease such as angina pectoris.
Diabetic nephropathy,
Left ventricular hypertrophy,
Raynaud phenomenon,
Silent myocardial ischemia

Mechanism of Action of amlodipine

In a normotensive person, vascular smooth muscle contraction initiates when calcium enters the cell via voltage-dependent L-type calcium channels. The calcium binds to intracellular calmodulin, which subsequently binds to and activates myosin light-chain kinase (MLCK).

The myosin light-chain kinase is responsible for the phosphorylation of myosin light-chain. This causes muscle contraction and vasoconstriction. This contraction becomes further amplified by calcium-induced calcium release from the sarcoplasmic reticulum. These events leads to a decreased vascular cross-sectional area, increased vascular resistance, and increased blood pressure.

Inhibits transmembrane influx of extracellular calcium ions across membranes of myocardial cells and vascular smooth muscle cells without changing serum calcium concentrations; this inhibits cardiac and vascular smooth muscle contraction, thereby dilating the main coronary and systemic arteries. Ultimately, this causes a decrease in blood pressure.

Amlodipine’s role in relieving stable angina is by lowering of afterload secondary to its vasodilatory and antihypertensive properties. Reducing afterload lowers the myocardial oxygen demand at any level of exertion because at this point the heart does not need to work as hard to pump blood into the systemic circulation.

Amlodipine also alleviates Prinzmetal or variant angina by blocking coronary spasm and restoring the normal blood flow in the coronary arteries that supply the heart muscles.

Absorption

Bioavailability: 64-90%

Onset: 24-96 hr

Duration: 24 hr (antihypertensive effect)

Peak plasma time: 6-12 hr

Steady-state plasma levels are reached after 7-8 days of consecutive dosing

Distribution

Protein-bound: 93-98%

Vd: 21 L/kg

Metabolism

Extensively metabolized in the liver by CYP3A4

Metabolites: Pyridine analog (inactive)

Elimination

Half-life: 30-50 hours.

The benefit of such a long half-life is the ability to have once-daily dosing.

Excretion: Urine (10% [parent]; 60% [inactive metabolites])

Pharmacokinetics

Amlodipine is well absorbed following oral administration with peak blood concentrations occurring after 6-12 hours. The bioavailability varies but is usually about 60-65%. Amlodipine is reported to be about 97.5% bound to plasma proteins.

It has a prolonged terminal elimination half-life of 35-50 hours and steady-state plasma concentrations are not achieved until 7-8 days of administration. Amlodipine is extensively metabolized in the liver, metabolites are mostly excreted in urine together with less than 10% of a dose as unchanged drug.

Dosage and administration of amlodipine

Amlodipine can be used as monotherapy or in combination with several different medications to manage hypertension or CAD in patients. Common combinations are:

Amlodipine/atorvastatin to reduce cardiovascular events.

Amlodipine/aliskiren

Amlodipine/benazepril or amlodipine/perindopril:

Amlodipine/olmesartan or amlodipine/telmisartan or amlodipine/valsartan

Recommended Dosages for hypertension

Adults: initial dose 5 mg once daily; maximum dose of 10 mg per day

Geriatric and Debilitated Patients: reduce initial dose to 2.5 mg once daily; maximum dose of 10 mg per day

Adolescents and Children 6 years of age or older: 2.5 to 5 mg once daily; maximum dose of 5 mg per day

Children 6 years of age or younger: 0.05 to 0.2 mg/kg per day; maximum dose 0.3 to 0.6 mg/kg per day (up to 20 mg per day)

Dosage for patients with CAD, Chronic Stable Angina, Prinzmental Angina, CAD Documented by Angiography and Without Heart Failure or Ejection Fraction less than 40%

Adults: initial dose 5 to 10 mg once daily

Elderly and debilitated patients: initial dose 5 mg once daily; usual dose is 10 mg once daily

Dosage for patients with Hepatic Impairment

Adults: initial dose of 2.5 mg once daily for hypertension or 5 mg once daily for angina. Adjust the dosage based on clinical response.

Precautions:

Amlodipine should be used with caution in patients with hypertension, in patients whose cardiac reserve is poor, and in those with heart failure since the deterioration of heart failure has been noted.

Amlodipine should not be used in cardiogenic shock, in patients who have recently suffered a myocardial infarction, or in acute unstable angina. Amlodipine should not be used to treat an angina attack in chronic stable angina.

In patients with severe aortic stenosis, amlodipine may increase the risk of developing heart failure. Sudden withdrawal may be associated with an exacerbation of angina.

The dose may need to be reduced in patients with hepatic impairment. Amlodipine should be discontinued in patients who experience ischaemic pain following its administration.

Adverse effects

The most common adverse effects of amlodipine are associated with its vasodilator action often diminish on continued therapy. They include dizziness, flushing, headache, hypotension, peripheral edema, tachycardia, and palpitations.

Nausea and other gastrointestinal disturbances, increased micturition frequency, lethargy, eye pain, and mental depression have also occurred.

A paradoxical increase in ischaemic chest pain may occur at the start of treatment and in a few patients, excessive fall in blood pressure has led to cerebral or myocardial ischemia or transient blindness.

There have been reports of rashes(including erythema multiforme), fever and abnormalities in liver function, including cholestasis due to hypersensitivity reactions. Gingival hyperplasia, myalgia, tremor, and impotence have been reported. Overdosage may be associated with bradycardia and hypotension.

Interactions

Amlodipine may advance antihypertensive drugs such as beta-blockers although the combination is well generally well tolerated. Enhanced antihypertensive effects may also be seen with concomitant use of drugs such as aldesleukin and antipsychotics that cause hypotension.

The drug may modify insulin and glucose responses and therefore diabetic patients may need to adjust their antidiabetic treatment when receiving amlodipine.


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