Amlodipine

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Amlodipine
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
AHFS/Drugs.commonograph
MedlinePlusa692044
Licence dataUS FDA:link
Pregnancy cat.C (AU) C (US)
Legal statusPOM (UK) -only (US)
RoutesOral (tablets)
Pharmacokinetic data
Bioavailability64 to 90%
MetabolismHepatic
Half-life30 to 50 hours
ExcretionRenal
Identifiers
CAS number88150-42-9 YesY
ATC codeC08CA01
PubChemCID 2162
DrugBankDB00381
ChemSpider2077 YesY
UNII1J444QC288 YesY
KEGGD07450 YesY
ChEBICHEBI:2668 YesY
ChEMBLCHEMBL1491 YesY
Chemical data
FormulaC20H25ClN2O5 
Mol. mass408.879 g/mol
 YesY (what is this?)  (verify)
 
  (Redirected from Norvasc)
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Amlodipine
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
AHFS/Drugs.commonograph
MedlinePlusa692044
Licence dataUS FDA:link
Pregnancy cat.C (AU) C (US)
Legal statusPOM (UK) -only (US)
RoutesOral (tablets)
Pharmacokinetic data
Bioavailability64 to 90%
MetabolismHepatic
Half-life30 to 50 hours
ExcretionRenal
Identifiers
CAS number88150-42-9 YesY
ATC codeC08CA01
PubChemCID 2162
DrugBankDB00381
ChemSpider2077 YesY
UNII1J444QC288 YesY
KEGGD07450 YesY
ChEBICHEBI:2668 YesY
ChEMBLCHEMBL1491 YesY
Chemical data
FormulaC20H25ClN2O5 
Mol. mass408.879 g/mol
 YesY (what is this?)  (verify)

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

Contents

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

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.

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

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.

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 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:

See also

References

  1. ^ "Amlodipine Besylate". The American Society of Health-System Pharmacists. http://www.amlodipinebesylatez.com/. 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. http://www.norvasc.com/high-blood-pressure-medicine/index.asp. Retrieved 20 July 2010. 
  4. ^ Sciencelab.com, Inc. (6 November 2008). "Material Safety Data Sheet: Amlodipine Besylate". Houston, Texas: ScienceLab.com. http://www.sciencelab.com/xMSDS-Amlodipine_Besylate-9922908. Retrieved 20 July 2010. 
  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. 
  6. ^ Beresford, AP; McGibney D, Humphrey MJ, Macrae PV, and Stopher DA (February 1988). "Metabolism and kinetics of amlodipine in man". Xenobiotica 18 (2): 245–254. doi:10.3109/00498258809041660. PMID 2967593. 
  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. 
  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. 
  9. ^ Kennedy, Val Brickates (2007-03-22). "Pfizer loses court ruling on Norvasc patent". MarketWatch. http://www.marketwatch.com/news/story/pfizer-loses-court-ruling-norvasc/story.aspx?guid=%7B9819D67E-B76B-431D-835C-FB8D6D8327B7%7D. 
  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. 

External links