Difference between revisions of "Amlodipine"

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{{Refimprove|date=May 2010}}
 
{{Refimprove|date=May 2010}}
 
{{drugbox | verifiedrevid = 321794363
 
{{drugbox | verifiedrevid = 321794363
−
|drug_name= Amlodipine
+
| drug_name= Amlodipine
−
|IUPAC_name = (''RS'')-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
+
| IUPAC_name = (''RS'')-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
−
|image=Amlodipine Structural Formulae.png
+
| image=Amlodipine Structural Formulae.png
 
| width = 400
 
| width = 400
 
| image2 = Amlodipine_3d_structure.png
 
| image2 = Amlodipine_3d_structure.png
Line 9: Line 9:
 
| imagename = 1 : 1 mixture (racemate)<br />
 
| imagename = 1 : 1 mixture (racemate)<br />
 
| CASNo_Ref = {{cascite}}
 
| CASNo_Ref = {{cascite}}
−
|CASNo_Ref = {{cascite}}
+
| CASNo_Ref = {{cascite}}
 
| InChI = 1/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
 
| InChI = 1/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
 
| InChIKey = HTIQEAQVCYTUBX-UHFFFAOYAV
 
| InChIKey = HTIQEAQVCYTUBX-UHFFFAOYAV
Line 19: Line 19:
 
| DrugBank=APRD00520
 
| DrugBank=APRD00520
 
| C=20 | H=25 | Cl=1 | N=2 | O=5
 
| C=20 | H=25 | Cl=1 | N=2 | O=5
−
|molecular_weight = 408.879 g/mol
+
| molecular_weight = 408.879 g/mol
 
| smiles = Clc1ccccc1C2C(=C(/N/C(=C2/C(=O)OCC)COCCN)C)\C(=O)OC
 
| smiles = Clc1ccccc1C2C(=C(/N/C(=C2/C(=O)OCC)COCCN)C)\C(=O)OC
−
|bioavailability = 64 to 90%
+
| bioavailability = 64 to 90%
−
|metabolism = [[Liver|Hepatic]]Nikhil and Nilesh filed a patent on amlodipine
+
| protein_bound =
−
|elimination_half-life = 30 to 50 hours
+
| metabolism = [[Liver|Hepatic]]
−
|excretion = [[Kidney|Renal]]
+
| elimination_half-life = 30 to 50 hours
−
|pregnancy_AU = C
+
| excretion = [[Kidney|Renal]]
−
|pregnancy_US = C
+
| pregnancy_AU = C
−
|legal_UK = POM
+
| pregnancy_US = C
−
|legal_US = Rx-only
+
| legal_UK = POM
−
|routes_of_administration = Oral (tablets)
+
| legal_US = Rx-only
 +
| routes_of_administration = Oral (tablets)
 
}}
 
}}
 
'''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 pectoris|angina]]. 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]].  
 
'''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 pectoris|angina]]. 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]].  
Line 36: Line 37:
 
* [[Hypertension]]
 
* [[Hypertension]]
 
* [[Angina pectoris]]
 
* [[Angina pectoris]]
−
 
−
==Cautions==
 
−
* [[hepatic]] impairment
 
−
* [[pregnancy]]
 
  
 
==Contraindications==
 
==Contraindications==
 +
 +
* [[breast feeding]]
 
* [[cardiogenic shock]]
 
* [[cardiogenic shock]]
 
* [[unstable angina]]
 
* [[unstable angina]]
−
* [[aortic stenosis]]
+
* [[aortic stenosis]]: amlodipine causes vasodilation, which can result in reduced cardiac output in patients with severe [[aortic stenosis]].
−
* [[breast feeding]]
+
  
−
Amlodipine causes vasodilatation, which in patients with severe [[aortic stenosis]], can result in reduced cardiac output.
+
==Cautions==
−
 
+
* [[hepatic]] impairment
−
There is not absolute consensus about the contraindication, because if the patient has hypertension, his stenosis cannot be very severe, otherwise he would not have sufficient output to allow hypertension.<ref>[http://nelh2004.sequence.co.uk/index.cfm?question=3476 Does it matter how severe is the stenosis?] NHS July 19, 2006</ref>
+
* [[pregnancy]]
  
−
==Side effects==
+
==Adverse effects==
−
Some side effects of the use of amlodipine may be:<ref>Source: [[Sandoz]] product information sheet</ref>
+
Adverse side effects of the use of amlodipine may be:<ref>Source: [[Sandoz]] product information sheet</ref>
−
* Very often: [[peripheral edema]] ([[foot|feet]] and [[ankle]]s) - in 1 of 10 users
+
* Very often: [[peripheral edema]] in 8.3% of users, [[Fatigue (medical)|fatigue]] in 4.5% of users<ref name=>{{cite web
 +
|author=[[Pfizer]]
 +
|date=February 2006
 +
|url=http://www.norvasc.com/high-blood-pressure-medicine/index.asp
 +
|title=NORVASC (amlodipine besylate): official site
 +
|publisher=[http://www.pfizer.com/home/ Pfizer Inc.]
 +
|location=[[New York City]], [[New York]]
 +
|accessdate=20 July 2010}}</ref>
 
* Often: [[dizziness]]; [[palpitations]]; [[muscle]]-, [[stomach]]- or [[headache]]; [[dyspepsia]]; [[nausea]] - in 1 in 100 users
 
* Often: [[dizziness]]; [[palpitations]]; [[muscle]]-, [[stomach]]- or [[headache]]; [[dyspepsia]]; [[nausea]] - in 1 in 100 users
 
* Sometimes: [[blood]] disorders, development of [[breast]]s in [[man|men]] ([[gynecomastia]]), [[impotence]], [[Clinical depression|depression]], [[insomnia]], [[tachycardia]], [[gingival enlargement]] - in 1 in 1,000 users,
 
* Sometimes: [[blood]] disorders, development of [[breast]]s in [[man|men]] ([[gynecomastia]]), [[impotence]], [[Clinical depression|depression]], [[insomnia]], [[tachycardia]], [[gingival enlargement]] - in 1 in 1,000 users,
 
* Rarely: erratic [[behavior]], [[hepatitis]], [[jaundice]] - in 1 in 10,000 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
 
* Very rarely: [[hyperglycemia]], [[tremor]], [[Stevens-Johnson syndrome]] - in 1 in 100,000 users
 +
 +
The [[Acute (medicine)|acute]] oral [[toxicity]] ([[Median lethal dose|LD50]]) of amlodipine in [[Mouse|mice]] is 37&nbsp;mg/kg.<ref name=Sciencelab>{{cite web
 +
|author=Sciencelab.com, Inc.
 +
|date=6 November 2008
 +
|url=http://www.sciencelab.com/xMSDS-Amlodipine_Besylate-9922908
 +
|title=Material Safety Data Sheet: Amlodipine Besylate
 +
|publisher=[http://www.sciencelab.com/ ScienceLab.com]
 +
|location=Houston, Texas
 +
|accessdate=20 July 2010}}</ref>
 +
 +
==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==
 
==Dose==
 +
The recommended starting dose for adults is 5&nbsp;mg once daily, up to a maximum dose of 10&nbsp;mg once daily. Small, fragile, or elderly patients, or patients with [[Cirrhosis|hepatic insufficiency]] may be started on 2.5&nbsp;mg once daily.<ref name=Pfizer2010>{{cite web
 +
|author=[[Pfizer]]
 +
|date=March 2010
 +
|url=http://www.pfizer.com/files/products/uspi_norvasc.pdf
 +
|title=Norvasc: highlights of prescribing information
 +
|publisher=[http://www.pfizer.com/home/ Pfizer Inc.]
 +
|location=[[New York City]], [[New York]]
 +
|accessdate=20 July 2010}}</ref>
 +
The recommended starting dose for [[pediatrics|pediatric]] patients is 2.5&nbsp;mg to 5&nbsp;mg once daily. Doses in excess of 5&nbsp;mg daily have not been studied in pediatric patients.<ref name=Pfizer2010/> Amlodipine is available as 2.5&nbsp;mg, 5&nbsp;mg, and 10&nbsp;mg tablets.<ref name=Pfizer2010/>
 +
 +
==Pharmacokinetics==
 +
===Drug metabolism and excretion===
 
{{Unreferenced section|date=May 2010}}
 
{{Unreferenced section|date=May 2010}}
−
*[[Hypertension]] or [[Angina pectoris|angina]]: 2.5 to 10 [[milligram|mg]] once daily (initial treatment can start as low as 2.5 [[milligram|mg]] per day, titrate up to 10&nbsp;mg/day as necessary).
+
Amlodipine is almost entirely metabolised to inactive metabolites. 10% of the parent substance and 60% of the [[metabolite]]s are excreted in urine.
 +
 
 +
==Stereoisomerism==
 +
[[File:(±)-Amlodipine Enantiomers Structural Formulae.png|thumb|right|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]<ref name=Luksa1997>{{cite journal
 +
|author=Luksa J, Josic D, Kremser M, Kopitar Z, Milutinovic S
 +
|title=Pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration
 +
|journal=Journal of Chromatography. B, Biomedical Sciences and Applications
 +
|volume=703
 +
|issue=1-2
 +
|pages=185–193
 +
|date=05 December 1997
 +
|doi=10.1016/S0378-4347(97)00394-0
 +
|pmid=9448075
 +
|url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TG9-3SB1205-P&_user=10&_coverDate=12%2F05%2F1997&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1406759908&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=d5aa524a9914d3213db06e74c87889d5
 +
|accessdate=20 July 2010}}</ref> A method for the semi-preparative chromatographic purification of the enantiomers (''S'')-(–)-amlodipine and (''R'')-(+)-amlodipine has been reported.<ref name="Lukša_2">{{cite journal
 +
|author=Luksa J, Josíc D, Podobnik B, Furlan B, Kremser M
 +
|title=Semi-preparative chromatographic purification of the enantiomers S-(-)-amlodipine and R-(+)-amlodipine
 +
|journal=Journal of Chromatography. B, Biomedical Sciences and Applications
 +
|volume=693
 +
|issue=2
 +
|pages=367–375
 +
|date=06 June 1997
 +
|doi=10.1016/S0378-4347(97)00069-8
 +
|pmid=9210441
 +
|url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TG9-3ST1TYG-3G&_user=10&_coverDate=06%2F06%2F1997&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1406760683&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=63439b9ecababf73b6fd7921dedd9467
 +
|accessdate=20 July 2010}}</ref>
 +
 
 +
==Preparations==
 +
[[Pfizer]] [[patent]] protection on Norvasc lasted until 2007. Total patent expiration occurred later in 2007.<ref>{{Cite news
 +
| last = Kennedy
 +
| first = Val Brickates
 +
| title = Pfizer loses court ruling on Norvasc patent
 +
| work = MarketWatch
 +
| date = 2007-03-22
 +
| url = http://www.marketwatch.com/news/story/pfizer-loses-court-ruling-norvasc/story.aspx?guid=%7B9819D67E-B76B-431D-835C-FB8D6D8327B7%7D
 +
}}</ref> A number of generic versions are available.
  
−
==Salts==
 
 
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.
 
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.
  
Line 80: Line 160:
 
}}</ref>
 
}}</ref>
  
−
==Drug metabolism and excretion==
+
===Brand names===
−
{{Unreferenced section|date=May 2010}}
+
−
Amlodipine is almost entirely metabolised to inactive metabolites. 10% of the parent substance and 60% of the [[metabolite]]s are excreted in urine.
+
−
 
+
−
== Stereoisomerism ==
+
−
[[File:(±)-Amlodipine Enantiomers Structural Formulae.png|thumb|right|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]<ref name="Lukša_1">
+
−
{{cite journal
+
−
| author = Luksa J, Josic D, Kremser M, Kopitar Z, Milutinovic S
+
−
| title = Pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration
+
−
| journal = Journal of Chromatography. B, Biomedical Sciences and Applications
+
−
| volume = 703
+
−
| issue = 1-2
+
−
| pages = 185–93
+
−
| year = 1997
+
−
| month = December
+
−
| pmid = 9448075
+
−
| doi = 10.1016/S0378-4347(97)00394-0
+
−
| url =
+
−
| issn =
+
−
| accessdate = 2010-04-28
+
−
}}</ref>. A method for the semi-preparative chromatographic purification of the enantiomers (''S'')-(–)-amlodipine and (''R'')-(+)-amlodipine has been reported.<ref name="Lukša_2">{{cite journal
+
−
| author = Luksa J, Josíc D, Podobnik B, Furlan B, Kremser M
+
−
| title = Semi-preparative chromatographic purification of the enantiomers S-(-)-amlodipine and R-(+)-amlodipine
+
−
| journal = Journal of Chromatography. B, Biomedical Sciences and Applications
+
−
| volume = 693
+
−
| issue = 2
+
−
| pages = 367–75
+
−
| year = 1997
+
−
| month = June
+
−
| pmid = 9210441
+
−
| doi = 10.1016/S0378-4347(97)00069-8
+
−
| url =
+
−
| issn =
+
−
| accessdate = 2010-04-28
+
−
}}</ref>
+
−
 
+
−
==Patent loss==
+
−
[[Pfizer]] [[patent]] protection on Norvasc lasted until 2007. Total patent expiration occurred later in 2007.<ref>{{Cite news
+
−
| last = Kennedy
+
−
| first = Val Brickates
+
−
| title = Pfizer loses court ruling on Norvasc patent
+
−
| work = MarketWatch
+
−
| date = 2007-03-22
+
−
| url = http://www.marketwatch.com/news/story/pfizer-loses-court-ruling-norvasc/story.aspx?guid=%7B9819D67E-B76B-431D-835C-FB8D6D8327B7%7D
+
−
}}</ref> A number of generic versions are available.
+
−
 
+
−
==Brand names==
+
 
{{Unreferenced section|date=May 2010}}
 
{{Unreferenced section|date=May 2010}}
 
Amlodipine is marketed as:
 
Amlodipine is marketed as:
−
* '''Norvasc''' by [[Pfizer]] in [[North America]], some European countries, China, and Japan
 
−
* '''Norvasc''' and '''Perivasc''' in [[Australia]]
 
−
* '''Istin''' in the [[United Kingdom]] and [[Ireland]]
 
 
* '''Agen''' by [[Zentiva]] in the [[Czech Republic]]
 
* '''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
 
* '''Amdipin''' in [[Colombia]] by Laboratorios Lafrancol
 
* '''Amlodine''' by Dainippon Sumitomo Pharmaceuticals in [[Japan]], and in [[Philippines]] by Westfield Pharmaceuticals, a division of InnoGen
 
* '''Amlodine''' by Dainippon Sumitomo Pharmaceuticals in [[Japan]], and in [[Philippines]] by Westfield Pharmaceuticals, a division of InnoGen
−
* '''Amdepin''' by Cadila Pharmaceuticals in [[India]]
+
* '''Amlopine''' in [[Thailand]] by Berlin (Thailand) Pharmaceutical Industry Co Ltd
 
* '''Dailyvasc''' by Xeno Pharmaceuticals
 
* '''Dailyvasc''' by Xeno Pharmaceuticals
−
* '''Aken''' in [[Mexico]] by Kendrick Farmaceutica
+
* '''Hipril''' is a combination of [[lisinopril]] with amlodipine (5&nbsp;mg each) in [[India]]
 +
* '''Istin''' in the [[United Kingdom]] and [[Ireland]]
 
* '''Lopin''' in [[Bangladesh]] by Edruc Ltd
 
* '''Lopin''' in [[Bangladesh]] by Edruc Ltd
−
* '''Amlopine''' in [[Thailand]] by Berlin (Thailand) Pharmaceutical Industry Co Ltd
+
* '''Norvasc''' by [[Pfizer]] in [[North America]], some European countries, China, and Japan
−
* '''Amcard''' in [[Bangladesh]] by Apex Pharma Ltd
+
* '''Norvasc''' and '''Perivasc''' in [[Australia]]
−
* '''Hipril''' is a combination of [[lisinopril]] with amlodipine (5&nbsp;mg each)  in [[India]] by [[velavan]]
+
  
 
==See also==
 
==See also==
Line 151: Line 185:
  
 
==External links==
 
==External links==
−
*[http://www.norvasc.com/ Norvasc]
+
* [http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=1466 Istin - Summary of Product Characteristics] from the electronic Medicines Compendium
−
*[http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=1466 Istin - Summary of Product Characteristics] from the electronic Medicines Compendium
+
 
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Amlodipine U.S. National Library of Medicine: Drug Information Portal - Amlodipine]  
 
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Amlodipine U.S. National Library of Medicine: Drug Information Portal - Amlodipine]  
  
Line 158: Line 191:
  
 
[[Category:Calcium channel blockers]]
 
[[Category:Calcium channel blockers]]
−
[[Category:Pfizer]]
 
 
[[Category:World Health Organization essential medicines]]
 
[[Category:World Health Organization essential medicines]]
 
[[Category:Pyridines]]
 
[[Category:Pyridines]]

Latest revision as of 15:32, 16 September 2010

Amlodipine
260px
260px
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
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[[Script error: No such module "String".]]
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  (verify)
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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

Contraindications

Cautions

Adverse effects

Adverse side effects of the use of amlodipine may be:[1]

The acute oral toxicity (LD50) of amlodipine in mice is 37 mg/kg.[3]

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.[4] 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.[4] Amlodipine is available as 2.5 mg, 5 mg, and 10 mg tablets.[4]

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][5] A method for the semi-preparative chromatographic purification of the enantiomers (S)-(–)-amlodipine and (R)-(+)-amlodipine has been reported.[6]

Preparations

Pfizer patent protection on Norvasc lasted until 2007. Total patent expiration occurred later in 2007.[7] 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.[8]

Brand names

Amlodipine is marketed as:

See also

References

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External links

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  1. ↑ Source: Sandoz product information sheet
  2. ↑ Pfizer (February 2006). "NORVASC (amlodipine besylate): official site". New York City, New York: Pfizer Inc. Retrieved 20 July 2010.  External link in |publisher= (help)
  3. ↑ Sciencelab.com, Inc. (6 November 2008). "Material Safety Data Sheet: Amlodipine Besylate". Houston, Texas: ScienceLab.com. Retrieved 20 July 2010.  External link in |publisher= (help)
  4. ↑ 4.0 4.1 4.2 Pfizer (March 2010). "Norvasc: highlights of prescribing information" (PDF). New York City, New York: Pfizer Inc. Retrieved 20 July 2010.  External link in |publisher= (help)
  5. ↑ Luksa J, Josic D, Kremser M, Kopitar Z, Milutinovic S (05 December 1997). "Pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration". Journal of Chromatography. B, Biomedical Sciences and Applications. 703 (1-2): 185–193. doi:10.1016/S0378-4347(97)00394-0. PMID 9448075. Retrieved 20 July 2010.  Check date values in: |date= (help)
  6. ↑ Luksa J, Josíc D, Podobnik B, Furlan B, Kremser M (06 June 1997). "Semi-preparative chromatographic purification of the enantiomers S-(-)-amlodipine and R-(+)-amlodipine". Journal of Chromatography. B, Biomedical Sciences and Applications. 693 (2): 367–375. doi:10.1016/S0378-4347(97)00069-8. PMID 9210441. Retrieved 20 July 2010.  Check date values in: |date= (help)
  7. ↑ Kennedy, Val Brickates (2007-03-22). "Pfizer loses court ruling on Norvasc patent". MarketWatch. 
  8. ↑ 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. 
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