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Amlodipine

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Amlodipine
Clinical data
Trade namesNorvasc
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
IUPHAR/BPS
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)
ChiralityRacemic mixture
  • 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 (as besylate, mesylate or maleate) is a medication used to lower blood pressure and prevent chest pain. It belongs to a group of medications known as dihydropyridine-type calcium channel blockers.[1][2] By widening of blood vessels it lowers blood pressure. In angina, amlodipine increases blood flow to the heart muscle to relieve pain due to angina.

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[3]

Medical uses

Amlodipine is used in the management of hypertension[4] and coronary artery disease (chronic stable angina, vasospastic angina, and angiographically documented CAD without heart failure or ejection fraction < 40%.)[5] It can be used as either monotherapy or combination therapy for the management of hypertension or coronary artery disease.[5] Amlodipine can be administered to adults and children 6–17 years of age.[5]

Contraindications

Absolute

Relative

Adverse effects

Adverse side effects of the use of amlodipine may include:[6][7]

Overdosage

See also: Calcium channel blocker toxicity

Although rare,[8] amlodipine overdose toxicity can result in widening of blood vessels, severe low blood pressure, and fast heart rate.[9][10]

Amlodipine toxicity is generally managed with the following measures:

Mechanism

Amlodipine inhibits the movement of calcium ions into vascular smooth muscle cells and cardiac muscle cells. 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. 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. 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. As a calcium channel blocker, amlodipine is expected to inhibit the currents of L-type Cav1.3 channels in the zona glomerulosa.[12][13]

The mechanisms by which amlodipine relieves angina include:

Amlodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid.[16]

Metabolism

Amlodipine has been studied in healthy volunteers following oral administration of 14C-labelled drug.[17] amlodipine is well absorbed by the oral route with a mean oral bioavailability around 60%. It is metabolized in the liver to inactive metabolites via CYP3A4. The half-life of amlodipine is about 30–50 hours, and steady-state plasma concentrations are achieved after 7 to 8 days of daily dosing. Renal elimination is the major route of excretion with about 60% of an administered dose recovered in urine, largely as inactive pyridine metabolites. However, renal impairment does not significantly influence amlodipine elimination.[18]

Interactions

  • CYP3A inhibitors: Co-administration of moderate to strong inhibitors of the cytochrome p450 enzyme CYP3A4 (such as itraconazole, clarithromycin) that metabolizes amlodipine in the liver may increase the plasma concentrations of amlodipine.[19]
  • CYP3A inducers: No data is currently available for co-administration of CYP3A4 inducers with amlodipine.[19]
  • Simvastatin: Co-administration of simvastatin at doses greater than 20 mg can lead to an increase in simvastatin plasma concentrations and increase risk of myopathy.[20]
  • Sildenafil: Co-administration of sildenafil can lead to an increased risk of hypotension.[19]
  • Tacrolimus: Co-administration of tacrolimus in patients with the CYP3A5*3 genetic polymorphism may increase tacrolimus plasma concentrations.[21]

Combination therapy

If monotherapy with amlodipine or candesartan is not sufficient to reach the reducing blood pressure target, a combination of amlodipine 5 mg and candesartan 8 mg can be effective, lowering blood pressure after 12 weeks in patients not adequately controlled by monotherapy. People suffering from high blood pressure and high cholesterol can also benefit from using a combination of amlodipine with atorvastatin.[22]

History

Pfizer's patent protection on Norvasc lasted until 2007; total patent expiration occurred later in 2007.[23] 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 salts. 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 inhibitor, have recently been confirmed in a prospective, observational, multicentre trial of 1250 hypertensive patients.[24]

See also

References

  1. ^ "Amlodipine: MedlinePlus Drug Information". www.nlm.nih.gov. Retrieved 21 May 2015.
  2. ^ Cash, Jill C.; Glass, Cheryl Anne (10 February 2014). Family Practice Guidelines, Third Edition. Springer Publishing Company. ISBN 9780826197825.
  3. ^ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved 10 May 2015.
  4. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ a b c "Norvasc Prescribing Information" (PDF).
  6. ^ a b c d e f g h "DailyMed - AMLODIPINE - amlodipine besylate tablet". dailymed.nlm.nih.gov. Retrieved 5 November 2015.
  7. ^ Munoz, Ricardo; Vetterly, Carol G.; Roth, Stephen J.; Cruz, Eduardo da (18 October 2007). Handbook of Pediatric Cardiovascular Drugs. Springer Science & Business Media. ISBN 9781846289538.
  8. ^ Aronson, J (2014). Side Effects of Drugs Annual 35. Elsevier. ISBN 978-0-444-62635-6.
  9. ^ a b c d "Norvasc tablets label-FDA" (PDF). Retrieved 2 November 2015.
  10. ^ a b c Pillay, V (2013). Modern Medical Toxicology 4th Ed. Jaypee. ISBN 978-93-5025-965-8.
  11. ^ Hui, David (2015). Approach to Internal Medicine: A Resource Book for Clinical Practice Fourth Edition. Springer. ISBN 978-3-319-11820-8.
  12. ^ Arcangelo, Virginia Poole; Peterson, Andrew M. (2006). Pharmacotherapeutics for Advanced Practice: A Practical Approach. Lippincott Williams & Wilkins. ISBN 9780781757843.
  13. ^ Ritter, James; Lewis, Lionel; Mant, Timothy; Ferro, Albert (11 December 2012). A Textbook of Clinical Pharmacology and Therapeutics, 5Ed. CRC Press. ISBN 9781444113006.
  14. ^ Li, Y. Robert (6 April 2015). Cardiovascular Diseases: From Molecular Pharmacology to Evidence-Based Therapeutics. John Wiley & Sons. ISBN 9780470915370.
  15. ^ LEARNING, JONES & BARTLETT; Bartlett, Jones and (15 July 2012). 2013 Nurse's Drug Handbook. Jones & Bartlett Publishers. ISBN 9781449642846.
  16. ^ Luther, James M. (2014). "Is there a new dawn for selective mineralocorticoid receptor antagonism?". Current Opinion in Nephrology and Hypertension. 23 (5): 456–461. doi:10.1097/MNH.0000000000000051. ISSN 1062-4821.
  17. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Brittain, Harry G. (9 May 2012). Profiles of Drug Substances, Excipients and Related Methodology. Academic Press. ISBN 9780123977564.
  19. ^ a b c "Pfizer Laboratories Div Pfizer Inc".
  20. ^ Research, Center for Drug Evaluation and. "Drug Safety and Availability - FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury". www.fda.gov. Retrieved 5 November 2015.
  21. ^ Zuo, Xiao-cong; Zhou, Ya-nan; Zhang, Bi-kui; Yang, Guo-ping; Cheng, Ze-neng; Yuan, Hong; Ouyang, Dong-sheng; Liu, Shi-kun; Barrett, Jeffrey S. (1 January 2013). "Effect of CYP3A5*3 Polymorphism on Pharmacokinetic Drug Interaction between Tacrolimus and Amlodipine". Drug Metabolism and Pharmacokinetics. 28 (5): 398–405. doi:10.2133/dmpk.DMPK-12-RG-148.
  22. ^ Delgado-Montero, Antonia; Zamorano, Jose L. (1 December 2012). "Atorvastatin calcium plus amlodipine for the treatment of hypertension". Expert Opinion on Pharmacotherapy. 13 (18): 2673–2685. doi:10.1517/14656566.2012.742064. ISSN 1465-6566.
  23. ^ Kennedy VB (22 March 2007). "Pfizer loses court ruling on Norvasc patent". MarketWatch.
  24. ^ 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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