Amlodipine

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by 4.14.167.60 (talk) at 17:25, 7 October 2017 (→‎Mechanism of action). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Amlodipine
Clinical data
Pronunciation/æmˈloʊdəˌpin/[1]
Trade namesNorvasc, others
AHFS/Drugs.comMonograph
MedlinePlusa692044
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability64–90%
Protein binding93% [2]
MetabolismLiver
MetabolitesVarious inactive pyrimidine metabolites
Onset of actionHighest availability 6–12 hours after oral dose
Elimination half-life30–50 hours
Duration of actionAt least 24 hours
ExcretionUrine
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
PDB ligand
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, sold under the brand name Norvasc among others, is a medication used to treat high blood pressure and coronary artery disease.[3] While calcium channel blockers are not typically recommended in heart failure, amlodipine may be used if other medications are not sufficient for high blood pressure or heart related chest pain.[4] Amlodipine is taken by mouth and has an effect for at least a day.[3]

Common side effects include: swelling, feeling tired, abdominal pain, and nausea.[3] Serious side effects may include low blood pressure or a heart attack.[3] It is unclear if use is safe during pregnancy or breastfeeding.[3] Doses should be decreased in people with liver problems and in elderly individuals.[3] Amlodipine is a long acting calcium channel blocker of the dihydropyridine type.[3] It works partly by increasing the size of arteries.[3]

Amlodipine was first patented in 1986 with commercial sale beginning in 1990.[5] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[6] It is available as a generic medication.[3] Wholesale cost in the developing world is 0.003 to 0.066 USD per day for a typical dose as of 2015.[7] In the United States, a month's supply costs less than 25 USD.[8]

Medical uses

Amlodipine is used in the management of hypertension[9] and coronary artery disease in people with either stable angina (where chest pain occurs mostly after physical or emotional stress)[10] or vasospastic angina (where it occurs in cycles) and without heart failure. It can be used as either monotherapy or combination therapy for the management of hypertension or coronary artery disease. Amlodipine can be administered to adults and children 6–17 years of age.[2]

Combination therapy

Amlodipine can be given as a combination therapy with a variety of medications:[11][3]

Contraindications

The only absolute contraindication to amlodipine is an allergy to amlodipine or any other dihydropyridines.[12] There are several other situations, however, where amlodipine generally should not be used. In patients with cardiogenic shock, where the heart's ventricles are not able to pump enough blood, calcium channel blockers exacerbate the situation by preventing the flow of calcium ions into cardiac cells, which is required for the heart to pump.[13] While it is generally safe to use in patients with aortic stenosis (narrowing of the aorta where it meets the left ventricle) since it doesn't inhibit the ventricle's function, it can still cause collapse in cases of severe stenosis.[14] In unstable angina (excluding variant angina), amlodipine can cause a reflex increase in cardiac contractility (how hard the ventricles squeeze) and heart rate, which together increase the demand for oxygen by the heart itself.[15] Patients with severe hypotension can have their low blood pressure exacerbated, and patients in heart failure can get pulmonary edema. Those with impaired liver function are unable to metabolize amlodipine to its full extent, giving it a longer half-life.[16][12]

Amlodipine's safety in pregnancy hasn't been established, although it is known that there is reproductive toxicity at high doses. It is unknown whether amlodipine enters the milk of breastfeeding mothers.[12][16]

Adverse effects

Some common dose-dependent side effects of amolodipine include vasodilatory effects peripheral edema, dizziness, palpitations, and flushing.[12][17] Peripheral edema (fluid accumulation in the tissues) occurs at rate of 10.8% at a 10 mg dose (versus 0.6% for placebos), and is three times more likely in women than in men.[2] Amlodipine causes more dilation in the arterioles and precapillary vessels than the postcapillary vessels and venules. The increased dilation allows for more blood, which is unable to push through to the relatively constricted postcapillary venules and vessels; the pressure caused much of the plasma to move into the interstitial space.[18] Amlodipine-association edema can be avoided by adding ACE inhibitors or angiontensin II.[3] na Of the other dose-dependent side effects, both palpitations (4.5% at 10 mg vs. 0.6% in placebos) and flushing (2.6% vs. 0%) occurred more often in women; dizziness (3.4% vs. 1.5%) had no sex-bias.[12][2]

Common but non-dose related side effects are fatigue (4.5% vs. 2.8% with a placebo), nausea (2.9% vs. 1.9%), abdominal pain (1.6% vs. 0.3%), and somnolence (1.4% vs. 0.6%).[12]Some side effects are quite rare, occurring less than 1% of the time: blood disorders, impotence, depression, peripheral neuropathy, insomnia, tachycardia, or gingival enlargement, hepatitis, and jaundice.[12][19][20]

Overdose

See also: Calcium channel blocker toxicity

Although rare,[21] amlodipine overdose toxicity can result in widening of blood vessels, severe low blood pressure, and fast heart rate.[22] Toxicity is generally managed with fluid replacement[23] monitoring ECG results, vital signs, respiratory system function, glucose levels, kidney function, electrolyte levels, and urine output.Vasopressors are also administered when low blood pressure is not alleviated by fluid resuscitation).[2][22]

Interactions

Several drugs interact with amplodipine to increase levels of amlodipine in the body. CYP3A inhibitors, by nature of inhibiting the enzyme that metabolizes amlodipine, CYP3A4, is one such drug. Others include the calcium-channel blocker diltiazem, the antibiotic clarithromycin, and possibly some antifungals.[2] Amlodipine also causes several drugs to increase in levels, including cyclosporine, simvastatin, and tacrolimus (the increase in the last one being more likely in people with CYP3A5*3 genetic polymorphisms).[24] When more than 20 mg of simvastatin, a lipid-lowering agent, is given with amlodipine, there is also an increased risk of myopathy.[25] Giving amlodipine with Viagra increases the risk of hypotension.[2][3]

Pharmacology

Mechanism of action

Amlodipine is an angioselective calcium channel blocker and inhibits the movement of calcium ions into vascular smooth muscle cells and cardiac muscle cells which inhibits the contraction of cardiac muscle and vascular smooth muscle cells. Amlodipine inhibits calcium ion influx across cell membranes, with a greater effect on vascular smooth muscle cells. This causes vasodilation and a reduction peripheral vascular resistance, thus lowering blood pressure. Its effects on cardiac muscle also prevent excessive constriction in the coronary arteries.[3]

Negative inotropic effects can be detected in vitro, but such effects have not been seen in intact animals at therapeutic doses. Among the two stereoisomers [R(+), S(–)], the (–) isomer has been reported to be more active than the (+) isomer.[26] Serum calcium concentration is not affected by amlodipine. And it specifically inhibits the currents of L-type Cav1.3 channels in the zona glomerulosa of the adrenal gland.[27][28]

The mechanisms by which amlodipine relieves angina are:

Amlodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid.[31]

Amlodipine and one of its major metabolites. The amine group is oxidated and the side ester chains are hydrolyzed.[32]

Pharmacokinetics

Amlodipine has been studied in healthy volunteers following oral administration of 14C-labelled drug.[33] Amlodipine is well absorbed by the oral route with a mean oral bioavailability around 60%; the half-life of amlodipine is about 30 h to 50 h, and steady-state plasma concentrations are achieved after 7 to 8 days of daily dosing. Its long half-life and high bioavailability are largely in part of its high pKa (8.6); it is ionized at physiological pH, and thus can strongly attract proteins.[2] It is slowly metabolized in the liver by CYP3A4, with its amine group being oxidized and its side ester chain being hydrolyzed, resulting in an inactive pyridine metabolite.[34] 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.[35]

History

Pfizer's patent protection on Norvasc lasted until 2007; total patent expiration occurred later in 2007.[36] 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 and perindopril, an angiotensin converting enzyme inhibitor, have recently been confirmed in a prospective, observational, multicentre trial of 1250 hypertensive patients.[37]

The medical form comes as besylate, mesylate or maleate.[38]

Veterinary use

Amlodipine is used to treat hypertension in cats and dogs.[39] In cats, it is considered to be the first line of treatment due to its high success rate and few side effects. Systemic hypertension in cats is often a sign of another illness, and amlodipine is most often given to cats with kidney disease,[40] which causes high blood pressure by increase local RAAS activity[41] Amlodipine decreases proteinuria in most cats with chronic kidney disease; and is sometimes given together with an ACE inhibitor, which prevents potential damage to the glomeruli. While amlodipine is used in dogs, it is often as add-on to ACE inhibitors, which are the first line of drugs for canine hypertension. Amlodipine is used more commonly to treat congestive heart failure in dogs, as well as mitral valve regurgitation. Side effects are quite rare, but cats on amlodipine have a possibility of developing azotemia (high concentration of nitrogen), hypokalemia, reflex tachycardia, lethargy, and weight loss. In dogs, it acts as a diuretic, and chronic use can lead to gingival hyperplasia.[42]

References

  1. ^ "Medical Definition of AMLODIPINE". www.merriam-webster.com. Archived from the original on 8 November 2016. Retrieved 5 July 2017. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  2. ^ a b c d e f g h "Norvasc Prescribing Information" (PDF). Archived from the original (PDF) on 16 February 2017. Retrieved 3 July 2017. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  3. ^ a b c d e f g h i j k l m "Amlodipine Besylate". Drugs.com. American Society of Hospital Pharmacists. Archived from the original on 4 June 2016. Retrieved 22 July 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  4. ^ The ESC Textbook of Preventive Cardiology: Clinical Practice. Oxford University Press. 2015. p. 261. ISBN 9780199656653. {{cite book}}: External link in |ref= (help)
  5. ^ Chorghade, Mukund S. (2006). Drug Discovery and Development. Vol. 1. Hoboken: John Wiley & Sons. p. 207. ISBN 9780471780090. Archived from the original on 15 August 2016. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  6. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived from the original (PDF) on 13 December 2016. Retrieved 8 December 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  7. ^ "Amlodipine". International Drug Price Indicator Guide. Archived from the original on 11 August 2017. Retrieved 23 July 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  8. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia (Deluxe Lab-Coat ed.). Jones & Bartlett Learning. p. 154. ISBN 9781284057560.
  9. ^ 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. PMC 2725792. PMID 19688100.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ MedlinePlus Encyclopedia: Stable angina
  11. ^ 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.Closed access icon
  12. ^ a b c d e f g "Amlodipine besylate tablet". DailyMed. US National Library of Medicine. Archived from the original on 29 October 2015. Retrieved 5 November 2015. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  13. ^ "Amlodipine Disease Interactions". Drugs.com. Archived from the original on 11 August 2017. Retrieved 4 July 2017. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  14. ^ Grimard, Brian H.; Safford, Robert E.; Burns, Elizabeth L. (2016). "Aortic Stenosis: Diagnosis and Treatment". American Family Physician. 93 (5): 371–378. ISSN 0002-838X. Archived from the original on 11 August 2017. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  15. ^ Hitchings, Andrew; Lonsdale, Dagan; Burrage, Daniel; Baker, Emma (2014). The Top 100 Drugs e-book: Clinical Pharmacology and Practical Prescribing. Elsevier Health Sciences. p. 90. ISBN 9780702055157. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  16. ^ a b "Amlodipine 5mg Tablets". emc. 30 May 2017. Archived from the original on 14 July 2017. Retrieved 3 July 2017. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  17. ^ Russell, R. P. (1988). "Side effects of calcium channel blockers" (PDF). Hypertension. 11 (3 Pt 2): II42. doi:10.1161/01.HYP.11.3_Pt_2.II42. ISSN 0194-911X. PMID 3280492. Archived from the original (PDF) on 11 August 2017. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  18. ^ Sica, Domenic A. (1 July 2003). "Calcium Channel Blocker-Related Peripheral Edema: Can It Be Resolved?". The Journal of Clinical Hypertension. 5 (4): 291–295. doi:10.1111/j.1524-6175.2003.02402.x. ISSN 1751-7176. Archived from the original on 11 August 2017. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  19. ^ Munoz, Ricardo; Vetterly, Carol G.; Roth, Stephen J.; Cruz, Eduardo da (18 October 2007). Handbook of Pediatric Cardiovascular Drugs. Springer Science & Business Media. p. 96. ISBN 9781846289538. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  20. ^ Ono, M.; et al. (2010). "Prevalence of Amlodipine-induced Gingival Overgrowth". Int J Oral-Med Sci. 9 (2): 96–100. doi:10.5466/ijoms.9.96. Retrieved 10 July 2017. {{cite journal}}: Explicit use of et al. in: |first1= (help)
  21. ^ Aronson, J (2014). Side Effects of Drugs Annual 35. Elsevier. ISBN 978-0-444-62635-6.
  22. ^ a b Pillay, V (2013). Modern Medical Toxicology (4th ed.). Jaypee. ISBN 978-93-5025-965-8.
  23. ^ Hui, David (2015). Approach to Internal Medicine: A Resource Book for Clinical Practice (4th ed.). Springer. ISBN 978-3-319-11820-8.
  24. ^ 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. (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. Archived from the original on 11 August 2017. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  25. ^ Center for Drug Evaluation and Research. "FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury". Drug Safety and Availability. FDA. Archived from the original on 6 January 2013. Retrieved 5 November 2015. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  26. ^ Karmoker, J.R.; Joydhar, P.; Sarkar, S.; Rahman, M. (2016). "Comparative in vitro evaluation of various commercial brands of amlodipine besylate tablets marketed in Bangladesh" (PDF). Asian Journal of Pharmaceutical and Health Sciences. 6: 1384–1389. Archived from the original (PDF) on 1 July 2016. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  27. ^ Arcangelo, Virginia Poole; Peterson, Andrew M. (2006). Pharmacotherapeutics for Advanced Practice: A Practical Approach. Lippincott Williams & Wilkins. ISBN 9780781757843. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  28. ^ Ritter, James; Lewis, Lionel; Mant, Timothy; Ferro, Albert (2012). A Textbook of Clinical Pharmacology and Therapeutics (5 ed.). CRC Press. ISBN 9781444113006. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  29. ^ Li, Y. Robert (2015). Cardiovascular Diseases: From Molecular Pharmacology to Evidence-Based Therapeutics. John Wiley & Sons. ISBN 9780470915370. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  30. ^ Learning, Jones; Learning, Bartlett (2012). 2013 Nurse's Drug Handbook. Jones & Bartlett Publishers. ISBN 9781449642846. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  31. ^ 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. PMC 4248353.
  32. ^ Zhu, Yanlin; Wang, Fen; Li, Quan; Zhu, Mingshe; Du, Alicia; Tang, Wei; Chen, Weiqing (1 February 2014). "Amlodipine Metabolism in Human Liver Microsomes and Roles of CYP3A4/5 in the Dihydropyridine Dehydrogenation". Drug Metabolism and Disposition. 42 (2): 245–249. doi:10.1124/dmd.113.055400. ISSN 0090-9556. PMID 24301608. Archived from the original on 11 August 2017. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  33. ^ Beresford, A. P.; McGibney, D.; Humphrey, M. J.; Macrae, P. V.; Stopher, D. A. (1 January 1988). "Metabolism and kinetics of amlodipine in man". Xenobiotica. 18 (2): 245–254. doi:10.3109/00498258809041660. ISSN 0049-8254. PMID 2967593.Closed access icon
  34. ^ Nayler, Winifred G. (2012). Amlodipine. Springer Science & Business Media. p. 105. ISBN 9783642782237. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  35. ^ Brittain, Harry G. (2012). Profiles of Drug Substances, Excipients and Related Methodology. Academic Press. ISBN 9780123977564. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  36. ^ Kennedy VB (22 March 2007). "Pfizer loses court ruling on Norvasc patent". MarketWatch. Archived from the original on 3 August 2008. {{cite news}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  37. ^ 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.
  38. ^ Campbell, Anthony K. Intracellular Calcium. John Wiley & Sons. p. 68. ISBN 9781118675526.
  39. ^ Papich, Mark G. (2007). "Amlodipine Besylate". Saunders Handbook of Veterinary Drugs (2nd ed.). St. Louis, Mo: Saunders/Elsevier. pp. 26–27. ISBN 9781416028888.
  40. ^ Diamondback Drugs. "Amlodipine in Veterinary Medicine". Archived from the original on 11 August 2017. Retrieved 29 June 2017. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  41. ^ Plumb, Donald C. (2011). "Amlodipine Besylate". Plumb's Veterinary Drug Handbook (7th ed.). Stockholm, Wisconsin; Ames, Iowa: Wiley. pp. 53–54. ISBN 9780470959640.
  42. ^ Forney, Barbara. "Amlodipine for Veterinary Use". Wedgewood Pharmacy. Archived from the original on 27 June 2017. Retrieved 29 June 2017. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Amlodipine&oldid=804236773"