Amlodipine

Amlodipine

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Systematic (IUPAC) name
(RS)-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
Clinical data
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of administration	Oral (tablets)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	64 to 90%
Metabolism	Hepatic
Biological half-life	30 to 50 hours
Excretion	Renal
Identifiers
CAS Number	88150-42-9
ATC code	C08CA01 (WHO)
PubChem	CID 2162
DrugBank	APRD00520
ChemSpider	2077
Chemical data
Formula	C20H25ClN2O5
Molar mass	408.879 g/mol[[]]
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Amlodipine (as besylate, mesylate or maleate) is a long-acting calcium channel blocker (dihydropyridine class) used as an anti-hypertensive and in the treatment of angina. Like other calcium channel blockers, amlodipine acts by relaxing the smooth muscle in the arterial wall, decreasing total peripheral resistance and hence reducing blood pressure; in angina it increases blood flow to the heart muscle.

Indications

• Hypertension
• Angina pectoris

Contraindications

• breast feeding
• cardiogenic shock
• unstable angina
• aortic stenosis: amlodipine causes vasodilation, which can result in reduced cardiac output in patients with severe aortic stenosis.

Cautions

• hepatic impairment
• pregnancy

Adverse effects

Adverse side effects of the use of amlodipine may be:

• Very often: peripheral edema in 8.3% of users, fatigue in 4.5% of users
• Often: dizziness; palpitations; muscle-, stomach- or headache; dyspepsia; nausea - in 1 in 100 users
• Sometimes: blood disorders, development of breasts in men (gynecomastia), impotence, depression, insomnia, tachycardia, gingival enlargement - in 1 in 1,000 users,
• Rarely: erratic behavior, hepatitis, jaundice - in 1 in 10,000 users
• Very rarely: hyperglycemia, tremor, Stevens-Johnson syndrome - in 1 in 100,000 users

The acute oral toxicity (LD50) of amlodipine in mice is 37 mg/kg.

Mechanism of action

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:

Exertional Angina

In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus lowers myocardial oxygen demand, at any given level of exercise.

Vasospastic Angina

Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal's or variant) angina.

Interactions

• In patients with severe coronary artery disease, amlodipine can increase the frequency and severity of angina or actually cause a heart attack on rare occasions. This phenomenon usually occurs when first starting amlodipine, or at the time of dosage increase.
• Excessive lowering of blood pressure during initiation of amlodipine treatment can occur, especially in patients already taking another blood pressure lowering medication. In rare instances, congestive heart failure has been associated with amlodipine, usually in patients already on a beta blocker.

Dose

The recommended starting dose for adults is 5 mg once daily, up to a maximum dose of 10 mg once daily. Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily. The recommended starting dose for pediatric patients is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients. Amlodipine is available as 2.5 mg, 5 mg, and 10 mg tablets.

Pharmacokinetics

Drug metabolism and excretion

Amlodipine is almost entirely metabolised to inactive metabolites. 10% of the parent substance and 60% of the metabolites are excreted in urine.

Stereoisomerism

File:(±)-Amlodipine Enantiomers Structural Formulae.png

Enantiomers of amlodipine

Amlodipine is a chiral calcium antagonist, currently on the market and in therapeutic use as a racemate [1:1 mixture of (R)-(+)- and (S)-(–)-amlodipine] A method for the semi-preparative chromatographic purification of the enantiomers (S)-(–)-amlodipine and (R)-(+)-amlodipine has been reported.

Preparations

Pfizer patent protection on Norvasc lasted until 2007. Total patent expiration occurred later in 2007. A number of generic versions are available.

In the United Kingdom tablets of amlodipine from different suppliers may contain different salts. The strength of the tablets is expressed in terms of amlodipine base, i.e., without the salt. Tablets containing different salts are therefore considered interchangeable.

The efficacy and tolerability of a fixed-dose combination of amlodipine 5 mg and perindopril 4 mg, an angiotensin converting enzyme (ACE) inhibitor, have recently been confirmed in a prospective, observational multicentre trial of 1250 hypertensive patients.

Brand names

Amlodipine is marketed as:

• Agen by Zentiva in the Czech Republic
• Aken in Mexico by Kendrick Farmaceutica
• Amcard in Bangladesh by Apex Pharma Ltd
• ATECARD-AM in India by Alembic Ltd
• Amdepin by Cadila Pharmaceuticals in India
• Amdipin in Colombia by Laboratorios Lafrancol
• Amlodine by Dainippon Sumitomo Pharmaceuticals in Japan, and in Philippines by Westfield Pharmaceuticals, a division of InnoGen
• Amlopine in Thailand by Berlin (Thailand) Pharmaceutical Industry Co Ltd
• Dailyvasc by Xeno Pharmaceuticals
• Hipril is a combination of lisinopril with amlodipine (5 mg each) in India
• Istin in the United Kingdom and Ireland
• Lopin in Bangladesh by Edruc Ltd
• Norvasc by Pfizer in North America, some European countries, China, and Japan
• Norvasc and Perivasc in Australia

See also

• Amlodipine/benazepril

External links

• Istin - Summary of Product Characteristics from the electronic Medicines Compendium
• U.S. National Library of Medicine: Drug Information Portal - Amlodipine

ar:أملوديبين uk:Амлодипін