Amlodipine

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Amlodipine
Amlodipine Structural Formulae.png
Amlodipine 3d structure.png
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.com monograph
MedlinePlus a692044
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes Oral (tablets)
Pharmacokinetic data
Bioavailability 64 to 90%
Metabolism Hepatic
Half-life 30 to 50 hours
Excretion Renal
Identifiers
CAS number 88150-42-9 YesY
ATC code C08CA01
PubChem CID 2162
DrugBank DB00381
ChemSpider 2077 YesY
UNII 1J444QC288 YesY
KEGG D07450 YesY
ChEBI CHEBI:2668 YesY
ChEMBL CHEMBL1491 YesY
Chemical data
Formula C20H25ClN2O5 
Mol. mass 408.879 g/mol
 YesY (what is this?)  (verify)

Amlodipine (Norvasc (Pfizer) and generics) (as besylate, mesylate or maleate) is a long-acting dihydropyridine-type (DHP) calcium channel blocker used to lower blood pressure and to treat anginal chest pain. Like other calcium channel blockers, amlodipine lowers blood pressure by relaxing arterial smooth muscles, which decreases total peripheral resistance and therefore reduces blood pressure. In angina, amlodipine increases blood flow to the heart muscle (although DHP-class calcium channel blockers are more selective for arteries than the muscular tissue of the heart (myocardium), as the calcium ion channels of the heart are not of the dihydropyridine-type).

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[1]

Medical uses[edit]

Amlodipine is used in the management of hypertension[2] and coronary artery disease.[3]

Contraindications[edit]

Adverse effects[edit]

Adverse side effects of the use of amlodipine may include:[4]

The acute oral toxicity (LD50) of amlodipine in mice is 37 mg/kg.[6]

Cautions[edit]

Interactions[edit]

  • 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.
  • 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.
  • Amlodipine is primarily metabolyzed by the liver, via the cytochrome P450 isoenzyme CYP3A4.[7] As a result, serum levels can potentially be affected by drugs which inhibit or activate CYP3A4. Grapefruit juice can inhibit the cytochrome P450 system,[7] but the predicted interaction risk with amlodipine is low.[8]

Mechanism of action[edit]

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the movement of calcium ions into vascular smooth muscle cells and cardiac muscle cells. 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, or decreased heart muscle contractility, 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 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. Also, as a calcium channel blocker amlodipine is expected to inhibit the currents of L-type Cav1.3 channels in the zona glomerulosa of the adrenal, reducing aldosterone production and corroborating to lower blood pressure.[9][10]

Amlodipine also acts as a functional inhibitor of acid sphingomyelinase (FIASMA).[11] Sphingomyelin is involved in signal transduction and programmed cell death.

The precise mechanisms by which amlodipine relieves angina is not fully understood, but are thought to include:

Stable angina
In patients with stable (exertional) angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, thereby lowering myocardial oxygen demand, at any given level of exercise.
Prinzmetal's angina
Amlodipine has been demonstrated to block spasm of the coronary arteries 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 Prinzmetal's angina.

Pharmacokinetics and metabolism[edit]

The metabolism and excretion of amlodipine have been studied in healthy volunteers following oral administration of 14C-labelled drug.[12] 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[edit]

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][13] A method for the semi-preparative chromatographic purification of the enantiomers (S)-(–)-amlodipine and (R)-(+)-amlodipine has been reported.[14]

Both enantiomers have different channel blocking activity.[15]

Preparations[edit]

Pfizer's patent protection on Norvasc lasted until 2007. Total patent expiration occurred later in 2007.[16] 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.[17]

Brand names[edit]

Amlodipine is marketed as:

  • Emadine in Nepal by Merck Kga by Merck Kga'
  • Aforbes by Merck Inc. Philippines
  • Agen by Zentiva in the Czech Republic
  • Aken in Mexico by Kendrick Farmaceutica
  • Amcard in Bangladesh by Apex Pharma Ltd
  • Amdepin by Cadila Pharmaceuticals in India
  • Amlod in Nepal
  • Amdipin in Colombia by Laboratorios Lafrancol
  • Amlodine by Dainippon Sumitomo Pharmaceuticals in Japan, and in Philippines by Westfield Pharmaceuticals, a division of InnoGen
  • Amlodipin in Norway
  • Amlodipine 5 in Indonesia by PT KALBE FARMA Tbk, Bekasi
  • Amlodipin-Mepha 5/10 in Switzerland by Mepha Pharma AG, Basel
  • Amlong in India by Micro Labs
  • Amlopin by Lek
  • Amlopin in Bangladesh by The Acme Laboratories Ltd
  • Amlopine in Thailand by Berlin (Thailand) Pharmaceutical Industry Co Ltd
  • Amlostin in the United Kingdom by Discovery Pharmaceuticals
  • Amlosun in Bangladesh by Sun Pharmaceutical (Bangladesh) Ltd
  • Amlovas in India by Macleods Pharmaceuticals Ltd
  • Amlovasc in the United Kingdom by Dr. Reddy's Laboratories
  • Amlozek in Poland by Adamed
  • Asomex by Emcure Pharmaceuticals India
  • Atecard-AM in India by Alembic Ltd
  • Camlodin in Bangladesh by Square Pharmaceuticals 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
  • Lama in India by Stadmed Private Limited, Kolkata
  • Lodopin in Pakistan by Merck Pakistan
  • Lopin in Bangladesh by Edruc Ltd
  • Lodip in Nepal by TIME Pharmaceuticals
  • Nelod in Bangladesh by The Kemiko Pharmaceuticals Ltd
  • Nopidin in Bangladesh by Ad-din Pharmaceuticals Ltd
  • Norvasc by Pfizer in North America, some European countries, China, Japan, Philippines, and Pakistan
  • Norvasc, Perivasc and Nordip in Australia
  • Pharex Amlodipine in the Philippines by PHAREX HealthCorp
  • Tenox by Krka
  • Spidip 5 in India by Spiritus Pharmaceuticals Pvt Ltd

See also[edit]

External inks[edit]

  • CVnor in Bangladesh by Navana pharmaceuticals Ltd

References[edit]

  1. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  2. ^ Wang, JG (2009). "A combined role of calcium channel blockers and angiotensin receptor blockers in stroke prevention". Vascular health and risk management 5: 593–605. doi:10.2147/vhrm.s6203. PMID 19688100. 
  3. ^ "Amlodipine Besylate". The American Society of Health-System Pharmacists. Retrieved 3 April 2011. 
  4. ^ Source: Sandoz product information sheet
  5. ^ Pfizer (February 2006). "Norvasc (amlodipine besylate): official site". New York City, New York: Pfizer Inc. Archived from the original on 2014-02-26. Retrieved 2014-02-26. 
  6. ^ Sciencelab.com, Inc. (6 November 2008). "Material Safety Data Sheet: Amlodipine Besylate". Houston, Texas: ScienceLab.com. Retrieved 20 July 2010. 
  7. ^ a b "Product Monograph:Norvasc" (PDF). Pfizer Canada Inc'. 2012. Retrieved 2013-03-24. 
  8. ^ Bailey DG, Dresser G, and Arnold JMA (2012). "Grapefruit and Medication Interactions: Forbidden Fruit or Avoidable Consequences?". Canadian Medical Association Journal. doi:10.1503/cmaj.120951. 
  9. ^ Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AE, Davenport AP, Dekkers T, Tops B, Küsters B, Ceral J, Yeo GS, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ. (2013). "Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension.". Nature Genetics 45 (9): 1055–1060. doi:10.1038/ng.2716. PMID 23913004. 
  10. ^ Felizola SJA, Maekawa T, Nakamura Y, Satoh F, Ono Y, Kikuchi K, Aritomi S, Ikeda K, Yoshimura M, Tojo K, Sasano H. (2014). "Voltage-gated calcium channels in the human adrenal and primary aldosteronism.". J Steroid Biochem Mol Biol. 144 (part B): 410–416. doi:10.1016/j.jsbmb.2014.08.012. PMID 25151951. 
  11. ^ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer TW, Spitzer GM, Liedl KR, Gulbins E, Tripal P (2011). "Identification of novel functional inhibitors of acid sphingomyelinase". PLoS ONE 6 (8): e23852. doi:10.1371/journal.pone.0023852. PMC 3166082. PMID 21909365. 
  12. ^ Beresford AP, McGibney D, Humphrey MJ, Macrae PV, Stopher DA (February 1988). "Metabolism and kinetics of amlodipine in man". Xenobiotica 18 (2): 245–54. doi:10.3109/00498258809041660. PMID 2967593. 
  13. ^ Luksa J, Josic D, Kremser M, Kopitar Z, Milutinovic S (December 1997). "Pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration". J. Chromatogr. B Biomed. Sci. Appl. 703 (1-2): 185–93. doi:10.1016/S0378-4347(97)00394-0. PMID 9448075. 
  14. ^ Luksa J, Josíc D, Podobnik B, Furlan B, Kremser M (June 1997). "Semi-preparative chromatographic purification of the enantiomers S-(-)-amlodipine and R-(+)-amlodipine". J. Chromatogr. B Biomed. Sci. Appl. 693 (2): 367–75. doi:10.1016/S0378-4347(97)00069-8. PMID 9210441. 
  15. ^ Zhang, Xiao-Ping ; Loke, Kit Ee ; Mital, Seema ; Chahwala, Suresh ; Hintze, Thomas H (February 2002). "Paradoxical Release of Nitric Oxide by an L-Type Calcium Channel Antagonist, the R+ Enantiomer of Amlodipine". Journal of Cardiovascular Pharmacology 39 (2): 208–214. doi:10.1097/00005344-200202000-00007. 
  16. ^ Kennedy VB (22 March 2007). "Pfizer loses court ruling on Norvasc patent". MarketWatch. 
  17. ^ 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[edit]