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'''Amlodipine''' ('''Norvasc''' (Pfizer) and generics) (as [[besylate]], [[mesylate]] or [[maleate]]) is a long-acting [[calcium channel blocker]] [[[dihydropyridine]] (DHP) class] used as an [[antihypertensive]] and in the treatment of [[angina pectoris]]. Like other calcium channel blockers, amlodipine acts by relaxing the [[smooth muscle]] in the [[Artery|arterial wall]], decreasing [[total peripheral resistance]] and hence reducing [[blood pressure]]; in angina, it increases blood flow to the [[Cardiac muscle|heart muscle]] (although DHP-class calcium channel blockers are more selective for arteries than myocardium, as the cardiac calcium channels are not of the dihydropyridine-type).
'''Amlodipine''' ('''Norvasc''' (Pfizer) and generics) (as [[besylate]], [[mesylate]] or [[maleate]]) is a long-acting [[calcium channel blocker]] [[dihydropyridine]] (DHP) class] used as an [[antihypertensive]] and in the treatment of [[angina pectoris]]. Like other calcium channel blockers, amlodipine acts by relaxing the [[smooth muscle]] in the [[Artery|arterial wall]], decreasing [[total peripheral resistance]] and hence reducing [[blood pressure]]; in angina, it increases blood flow to the [[Cardiac muscle|heart muscle]] (although DHP-class calcium channel blockers are more selective for arteries than myocardium, as the cardiac calcium channels are not of the dihydropyridine-type).


==Medical uses==
==Medical uses==

Revision as of 00:16, 11 December 2012

Amlodipine
Clinical data
AHFS/Drugs.comMonograph
MedlinePlusa692044
License data
Pregnancy
category
  • AU: C
Routes of
administration		Oral (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability64 to 90%
MetabolismHepatic
Elimination half-life30 to 50 hours
ExcretionRenal
Identifiers
  • (RS)-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.102.428 Edit this at Wikidata
Chemical and physical data
FormulaC20H25ClN2O5
Molar mass408.879 g/mol g·mol−1
3D model (JSmol)
  • Clc1ccccc1C2C(=C(/N/C(=C2/C(=O)OCC)COCCN)C)\C(=O)OC
  • InChI=1S/C20H25ClN2O5/c1-4-28-20(25)18-15(11-27-10-9-22)23-12(2)16(19(24)26-3)17(18)13-7-5-6-8-14(13)21/h5-8,17,23H,4,9-11,22H2,1-3H3 checkY
  • Key:HTIQEAQVCYTUBX-UHFFFAOYSA-N checkY
  (verify)

Amlodipine (Norvasc (Pfizer) and generics) (as besylate, mesylate or maleate) is a long-acting calcium channel blocker dihydropyridine (DHP) class] used as an antihypertensive and in the treatment of angina pectoris. 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 (although DHP-class calcium channel blockers are more selective for arteries than myocardium, as the cardiac calcium channels are not of the dihydropyridine-type).

Medical uses

Amlodipine is used in the management of hypertension and coronary artery disease.[1]

Contraindications

Adverse effects

Adverse side effects of the use of amlodipine may be:[2]

The acute oral toxicity (LD50) of amlodipine in mice is 37 mg/kg.[4]

Cautions

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. [citation needed]
  • Excessive lowering of blood pressure during initiation of amlodipine treatment can occur, especially in patients already taking another medication for lowering blood pressure. In rare instances, congestive heart failure has been associated with amlodipine, usually in patients already on a beta blocker.

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 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.

Amlodipine does also act as a functional inhibitor of acid sphingomyelinase (FIASMA).[5]

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

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, so 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.

Pharmacokinetics and metabolism

The metabolism and excretion of amlodipine have been studied in healthy volunteers following oral administration of 14C-labelled drug.[6] Amlodipine is well absorbed by the oral route with a mean oral bioavailability of approximately 60%. Renal elimination is the major route of excretion with about 60% of an administered dose recovered in urine, largely as inactive pyridine metabolites. The major metabolite identified was 2-([4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl- 2-pyridyl]methoxy) acetic acid, and this represented 33% of urinary radioactivity. Amlodipine concentrations in plasma declined with a mean half-life of 33 h, while elimination of total drug-related material from plasma was slower.

Stereoisomerism

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][7] A method for the semi-preparative chromatographic purification of the enantiomers (S)-(–)-amlodipine and (R)-(+)-amlodipine has been reported.[8]

Preparations

Pfizer's patent protection on Norvasc lasted until 2007. Total patent expiration occurred later in 2007.[9] 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.[10]

Brand names

Amlodipine is marketed as:

  • Amlovas in India by Macleods Pharmaceticals Ltd
  • Nelod in Bangladesh by The Kemiko Pharmaceuticals Ltd
  • Amlopin in Bangladesh by The Acme Laboratories Ltd
  • Amlosun in Bangladesh by Sun Pharmaceutical (Bangladesh) Ltd
  • Nopidin in Bangladesh by Ad-din Pharmaceuticals Ltd
  • Camlodin in Bangladesh by Square Pharmaceuticals Ltd
  • 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
  • Asomex by Emcure Pharmaceuticals India
  • Amdipin in Colombia by Laboratorios Lafrancol
  • Amlopin by Lek
  • 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
  • Amlodipine 5 in Indonesia by PT KALBE FARMA Tbk, Bekasi
  • Amlozek in Poland by Adamed
  • 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
  • Lodopin in Pakistan by Merck Pakistan
  • Norvasc by Pfizer in North America, some European countries, China, Japan, and Pakistan
  • AFORBES by Merck Inc. Philippines
  • Norvasc, Perivasc and Nordip in Australia
  • Tenox by Krka
  • Amlovasc in the United Kingdom by Dr. Reddy's Laboratories
  • LAMA in India by Stadmed Private Limited, Kolkata
  • PHAREX Amlodipine in the Philippines by PHAREX HealthCorp
  • AMLOSTIN in the United Kingdom by Discovery Pharmaceuticals
  • AMLONG in India by Micro Labs

See also

References

  1. ^ "Amlodipine Besylate". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  2. ^ Source: Sandoz product information sheet
  3. ^ Pfizer (February 2006). "Norvasc (amlodipine besylate): official site". New York City, New York: Pfizer Inc. Archived from the original on 24 July 2010. Retrieved 20 July 2010. {{cite web}}: External link in |publisher= (help); Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  4. ^ Sciencelab.com, Inc. (6 November 2008). "Material Safety Data Sheet: Amlodipine Besylate". Houston, Texas: ScienceLab.com. Retrieved 20 July 2010. {{cite web}}: External link in |publisher= (help)
  5. ^ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P (2011). "Identification of novel functional inhibitors of acid sphingomyelinase". PLoS ONE. 6 (8): e23852. doi:10.1371/journal.pone.0023852.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  6. ^ Beresford, AP (1988). "Metabolism and kinetics of amlodipine in man". Xenobiotica. 18 (2): 245–254. doi:10.3109/00498258809041660. PMID 2967593. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  7. ^ Luksa J, Josic D, Kremser M, Kopitar Z, Milutinovic S (5 December 1997). "Pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration". Journal of Chromatography B. 703 (1–2): 185–193. doi:10.1016/S0378-4347(97)00394-0. PMID 9448075.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Luksa J, Josíc D, Podobnik B, Furlan B, Kremser M (6 June 1997). "Semi-preparative chromatographic purification of the enantiomers S-(–)-amlodipine and R-(+)-amlodipine". Journal of Chromatography B. 693 (2): 367–375. doi:10.1016/S0378-4347(97)00069-8. PMID 9210441.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Kennedy, Val Brickates (22 March 2007). "Pfizer loses court ruling on Norvasc patent". MarketWatch.
  10. ^ Bahl VK, Jadhav UM, Thacker HP (2009). "Management of hypertension with the fixed combination of perindopril and amlodipine in daily clinical practice: results from the STRONG prospective, observational, multicenter study". Am J Cardiovasc Drugs. 9 (3): 135–42. doi:10.2165/00129784-200909030-00001. PMID 19463019.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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