Amlodipine

Amlodipine
Names
Pronunciation/æmˈloʊdɪˌpiːn/[1]
Trade namesNorvasc, others
IUPAC name
  • (RS)-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
Clinical data
Drug classCalcium channel blocker
Main usesHigh blood pressure, coronary artery disease[2]
Side effectsSwelling, feeling tired, abdominal pain, nausea[2]
Pregnancy
category
  • AU: C[3]
  • US: C (Risk not ruled out)[3]
    Routes of
    use    		By mouth
    Onset of actionHighest availability 6–12 hours after oral dose
    Duration of actionAt least 24 hours
    Defined daily dose5 mg[4]
    External links
    AHFS/Drugs.comMonograph
    US NLMAmlodipine
    MedlinePlusa692044
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability64–90%
    Protein binding93% [7]
    MetabolismLiver
    MetabolitesVarious inactive pyrimidine metabolites
    Elimination half-life30–50 hours
    ExcretionUrine
    Chemical and physical data
    FormulaC20H25ClN2O5
    Molar mass408.88 g·mol−1
    3D model (JSmol)
    ChiralityRacemic mixture
    SMILES
    • Clc1ccccc1C2/C(C(=O)OC)=C(/C)N/C(COCCN)=C2/C(=O)OCC
    InChI
    • 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

    Amlodipine, sold under the brand name Norvasc among others, is a medication used to treat high blood pressure and coronary artery disease.[2] While not typically recommended in heart failure, amlodipine may be used if other medications are not sufficient for treating high blood pressure or heart-related chest pain.[8] It is taken by mouth and has an effect that lasts for at least a day.[2]

    Common side effects include swelling, feeling tired, abdominal pain, and nausea.[2] Serious side effects may include low blood pressure or heart attack.[2] Whether use is safe during pregnancy or breastfeeding is unclear.[3][2] When used by people with liver problems, and in elderly individuals, doses should be reduced.[2] Amlodipine works partly by increasing the size of arteries.[2] It is a long-acting calcium channel blocker of the dihydropyridine type.[2]

    Amlodipine was patented in 1982, and approved for medical use in 1990.[9] It is on the World Health Organization's List of Essential Medicines.[10] It is available as a generic medication.[2] Wholesale cost in the developing world is US$0.003 to 0.066 per day for a typical dose as of 2015.[11] In the United States, a month's supply costs less than $25.[12] In 2017, it was the fifth most commonly prescribed medication in the United States, with more than 72 million prescriptions.[13][14]

    Medical uses

    Amlodipine is used in the management of hypertension[15] and coronary artery disease in people with either stable angina (where chest pain occurs mostly after physical or emotional stress)[16] 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.[7] Calcium channel blockers, including amlodipine, may provide greater protection against stroke than other classes of blood pressure-lowering medications.[17]

    Amlodipine along with other calcium channel blockers are considered the first choice in the pharmacological management of Raynaud's phenomenon.[18]

    Dosage

    The defined daily dose is 5 mg (by mouth).[4] In adults it is typically started at 5 mg by mouth once per day and may be increased to 10 mg once per day.[19] In older people or those with liver problems it should be started at 2.5 mg once per day.[19]

    Combination therapy

    Amlodipine can be given as a combination therapy with a variety of medications:[2][20]

    Contraindications

    The only absolute contraindication to amlodipine is an allergy to amlodipine or any other dihydropyridines.[7]

    Other situations occur, 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.[21] While use in patients with aortic stenosis (narrowing of the aorta where it meets the left ventricle) since it does not inhibit the ventricle's function is generally safe, it can still cause collapse in cases of severe stenosis.[22] 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.[23] 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 than typical.[7][24]

    Amlodipine's safety in pregnancy has not been established, although reproductive toxicity at high doses is known. Whether amlodipine enters the milk of breastfeeding mothers is also unknown.[7][24]

    Those who have heart failure, or recently had a heart attack, should take amlodipine with caution.[25]

    Side effects

    Drug-induced subacute lupus erythematosus: Erythematous and scaly plaque on a left posterior arm

    Some common dose-dependent adverse effects of amlodipine include vasodilatory effects, peripheral edema, dizziness, palpitations, and flushing.[7][26] 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.[7] It 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 causes much of the plasma to move into the interstitial space.[27] Amlodipine-association edema can be avoided by adding ACE inhibitors or angiontensin II receptor antagonist.[2] Of the other dose-dependent side effects, 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.[7]

    Common but not dose-related adverse 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%).[7] Side effects occurring less than 1% of the time include: blood disorders, impotence, depression, peripheral neuropathy, insomnia, tachycardia, gingival enlargement, hepatitis, and jaundice.[7][28][29]

    Amlodipine-associated gingival overgrowth is a relatively common side effect with exposure to amlodipine.[30] Poor dental health and buildup of dental plaque are risk factors.[30]

    Amlodipine may increase the risk of worsening angina or acute myocardium infarction, especially in those with severe obstructive coronary artery disease, upon dosage initiation or increase. However, depending on the situation, Amlodipine inhibits constriction and restores blood flow in coronary arteries as a result of its property that works directly on vascular smooth muscle causing reduction in peripheral vascular resistance and consequent reduction in blood pressure.[2]

    Overdose

    See also: Calcium channel blocker toxicity

    Although rare,[31] amlodipine overdose toxicity can result in widening of blood vessels, severe low blood pressure, and fast heart rate.[32] Toxicity is generally managed with fluid replacement[33] 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.[7][32]

    Interactions

    Several drugs interact with amlodipine to increase its levels in the body. CYP3A inhibitors, by nature of inhibiting the enzyme that metabolizes amlodipine, CYP3A4, are one such class of drugs. Others include the calcium-channel blocker diltiazem, the antibiotic clarithromycin, and possibly some antifungals.[7] Amlodipine 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).[34] When more than 20 mg of simvastatin, a lipid-lowering agent, are given with amlodipine, the risk of myopathy increases.[35] Giving amlodipine with Viagra increases the risk of hypotension.[7][2]

    Pharmacology

    Amlodipine is a long acting calcium channel antagonist that selectively inhibits calcium ion influx across cell membranes.[36] It targets L-type calcium channels in muscle cells and N-type calcium channels in the central nervous system which are involved in nociceptive signalling and pain perception.[37][38] Amlodipine has an inhibitory effect on calcium influx in smooth muscle cells to inhibit contraction.

    Amlodipine ends up significantly reducing total vascular resistance without decreasing cardiac output expressed by pressure-rate product and cardiac contractability in comparison with verapamil, a non-dihydropyridine.[39] In turn, following treatment lasting a month, with amlodipine, cardiac output was significantly enhanced.[39] Unlike verapamil which has efficacy in moderation of emotional arousal and reduces cardiac load without lowering cardiac output demands, amlodipine increases the cardiac output response concomitantly with increased functional cardiac load.[39]

    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 in peripheral vascular resistance, thus lowering blood pressure. Its effects on cardiac muscle also prevent excessive constriction in the coronary arteries.[2]

    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.[40] 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.[41][42]

    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.[45]

    Pharmacokinetics

    Amlodipine and one of its major metabolites: The nitrogen-containing ring is oxidized, and two of the side chains are hydrolyzed.[46]

    Amlodipine has been studied in healthy volunteers following oral administration of 14C-labelled drug.[47] 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. In the blood it has high plasma protein binding of 97.5%.[37] 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.[7] 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.[48] 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.[49] 20-25% of the drug is excreted in the faeces.[50]

    History

    Pfizer's patent protection on Norvasc lasted until 2007; total patent expiration occurred later in 2007.[51] 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. Fixed-dose combination of amlodipine and perindopril, an angiotensin converting enzyme inhibitor are also available.[52]

    The medical form comes as besylate, mesylate or maleate.[53]

    Society and culture

    Cost

    Wholesale cost in the developing world is US$0.003 to 0.066 per day for a typical dose as of 2015.[11] In the United States, a month's supply costs less than $25.[12] In 2017, it was the fifth most commonly prescribed medication in the United States, with more than 72 million prescriptions.[13][14] As of 2020, one month supply of 5mg amlodipine costs the NHS in the UK less than £1.[54]

    • Amlodipine costs (DrugStats)
    • Amlodipine prescriptions (DrugStats)

    Formulations

    Brands include Istin.[54] Amlodipine is also available combined with valsartan.[54]

    Veterinary use

    Amlodipine is most often used to treat systemic hypertension in cats and dogs.[55] In cats, it is the first line of treatment due to its efficacy and few side effects.[56] Systemic hypertension in cats is usually secondary to another abnormality, such as chronic kidney disease, and so amlodipine is most often administered to cats with kidney disease.[57] While amlodipine is used in dogs with systemic hypertension, it is not as efficacious. Amlodipine is also used to treat congestive heart failure due to mitral valve regurgitation in dogs.[58] By decreasing resistance to forward flow in the systemic circulation it results in a decrease in regurgitant flow into the left atrium.[59] Similarly, it can be used on dogs and cats with left-to-right shunting lesions such as ventricular septal defect to reduce the shunt. Side effects are rare in cats. In dogs, the primary side effect is gingival hyperplasia.[60]

    References

    1. ↑ "Medical Definition of AMLODIPINE". www.merriam-webster.com. Archived from the original on 8 November 2016. Retrieved 5 July 2017.
    2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "Amlodipine Besylate". Drugs.com. American Society of Hospital Pharmacists. Archived from the original on 4 June 2016. Retrieved 22 July 2016.
    3. 1 2 3 "Amlodipine Use During Pregnancy". Drugs.com. 28 October 2019. Archived from the original on 28 December 2019. Retrieved 29 December 2019.
    4. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 7 October 2020. Retrieved 21 September 2020.
    5. ↑ "Poisons Standard June 2017". legislation.gov.au. Archived from the original on 13 December 2020. Retrieved 7 January 2018.
    6. ↑ "Archived copy". Archived from the original on 1 February 2014. Retrieved 3 July 2017.{{cite web}}: CS1 maint: archived copy as title (link)
    7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "Norvasc- amlodipine besylate tablet". DailyMed. 14 March 2019. Archived from the original on 10 June 2020. Retrieved 29 December 2019.
    8. ↑ The ESC Textbook of Preventive Cardiology: Clinical Practice. Oxford University Press. 2015. p. 261. ISBN 9780199656653. {{cite book}}: External link in |ref= (help)
    9. ↑ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 465. ISBN 9783527607495. Archived from the original on 27 August 2021. Retrieved 1 June 2020.
    10. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
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    15. ↑ 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.
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    30. 1 2 Gaur S, Agnihotri R (June 2018). "Is dental plaque the only etiological factor in Amlodipine induced gingival overgrowth? A systematic review of evidence". J Clin Exp Dent. 10 (6): e610–e619. doi:10.4317/jced.54715. PMC 6005094. PMID 29930781.
    31. ↑ Aronson, J (2014). Side Effects of Drugs Annual 35. Elsevier. ISBN 978-0-444-62635-6.
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    45. ↑ 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. PMID 24992570.
    46. ↑ 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. S2CID 329321.
    47. ↑ 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
    48. ↑ Nayler, Winifred G. (2012). Amlodipine. Springer Science & Business Media. p. 105. ISBN 9783642782237. Archived from the original on 8 September 2017.
    49. ↑ Brittain, Harry G. (2012). Profiles of Drug Substances, Excipients and Related Methodology. Academic Press. ISBN 9780123977564. Archived from the original on 8 September 2017.
    50. ↑ Murdoch, David; Heel, Rennie C. (March 1991). "Amlodipine". Drugs. 41 (3): 478–505. doi:10.2165/00003495-199141030-00009. PMID 1711448.
    51. ↑ Kennedy VB (22 March 2007). "Pfizer loses court ruling on Norvasc patent". MarketWatch. Archived from the original on 3 August 2008.
    52. ↑ Multum Consumer Information on amlodipine and perindopril. Accessed 2020-02-28.
    53. ↑ Campbell, Anthony K. (14 October 2014). Intracellular Calcium. John Wiley & Sons. p. 68. ISBN 9781118675526. Archived from the original on 1 January 2021. Retrieved 10 August 2016.
    54. 1 2 3 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2021 – March 2021. p. 168-169. ISBN 978-0-85711-369-6.
    55. ↑ Papich, Mark G. (2007). "Amlodipine Besylate". Saunders Handbook of Veterinary Drugs (2nd ed.). St. Louis, Mo: Saunders/Elsevier. pp. 26–27. ISBN 9781416028888.
    56. ↑ Henik, RA; Snyder, PS; Volk, LM (28 August 2014). "Treatment of systemic hypertension in cats with amlodipine besylate". Journal of the American Animal Hospital Association. 33 (3): 226–234. doi:10.5326/15473317-33-3-226. PMID 9138233.
    57. ↑ Diamondback Drugs. "Amlodipine in Veterinary Medicine". Archived from the original on 11 August 2017. Retrieved 29 June 2017.
    58. ↑ Atkins, C.; Bonagura, J.; Ettinger, S.; Fox, P.; Gordon, S.; Haggstrom, J.; Hamlin, R.; Keene, B.; Luis-Fuentes, V. (1 November 2009). "Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease". Journal of Veterinary Internal Medicine. 23 (6): 1142–1150. doi:10.1111/j.1939-1676.2009.0392.x. ISSN 1939-1676. PMID 19780929.
    59. ↑ Suzuki, Shuji; Fukushima, Ryuji; Ishikawa, Taisuke; Yamamoto, Yuta; Hamabe, Lina; Kim, Soomin; Yoshiyuki, Rieko; Machida, Noboru; Tanaka, Ryou (18 September 2012). "Comparative effects of amlodipine and benazepril on Left Atrial Pressure in Dogs with experimentally-induced Mitral Valve Regurgitation". BMC Veterinary Research. 8: 166. doi:10.1186/1746-6148-8-166. ISSN 1746-6148. PMC 3489586. PMID 22989022.
    60. ↑ Forney, Barbara. "Amlodipine for Veterinary Use". Wedgewood Pharmacy. Archived from the original on 27 June 2017. Retrieved 29 June 2017.
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