|Trade names||Norvasc, others|
|Drug class||Calcium channel blocker|
|Protein binding||93% |
|Metabolites||Various inactive pyrimidine metabolites|
|Onset of action||Highest availability 6–12 hours after oral dose|
|Elimination half-life||30–50 hours|
|Duration of action||At least 24 hours|
|Chemical and physical data|
|Molar mass||408.879 g/mol|
|3D model (JSmol)|
Amlodipine, sold under the brand name Norvasc among others, is a medication used to treat high blood pressure and coronary artery disease. While 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. Amlodipine is taken by mouth and has an effect for at least a day.
Common side effects include swelling, feeling tired, abdominal pain, and nausea. Serious side effects may include low blood pressure or a heart attack. Whether use is safe during pregnancy or breastfeeding is unclear. When used by people with liver problems, and in elderly individuals, doses should be decreased. Amlodipine works partly by increasing the size of arteries. It is a long-acting calcium channel blocker of the dihydropyridine (DHP) type.
Amlodipine was first patented in 1986 with commercial sale beginning in 1990. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication. Wholesale cost in the developing world is US$0.003 to 0.066 per day for a typical dose as of 2015. In the United States, a month's supply costs less than $25.
Amlodipine is used in the management of hypertension and coronary artery disease in people with either stable angina (where chest pain occurs mostly after physical or emotional stress) 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.
- Amlodipine/atorvastatin, where amlodipine is given for hypertension or CAD and atorvastatin prevents cardiovascular events, or if the person also has high cholesterol.
- Amlodipine/aliskiren or amlodipine/aliskiren/hydrochlorothiazide if amlodipine alone cannot reduce blood pressure. Aliskiren is a renin inhibitor, which works to reduce primary hypertension (that with no known cause) by binding to renin and preventing it from initiating the renin–angiotensin system (RAAS) pathway to increase blood pressure. Hydrochlorothiazide is a diuretic and decreases overall blood volume.
- Amlodipine/benazepril if either drug has failed individually, or amlodipine alone caused edema. Benazepril is an ACE inhibitor and blocks the conversion of angiotensin I to angiotensin II in the RAAS pathway.
- Amlodipine/olmesartan or amlodipine/olmesartan/hydrochlorothiazide if amlodipine is insufficient in reducing blood pressure. Olmesartan is an angiotensin II receptor antagonist and blocks part of the RAAS pathway.
- Amlodipine/perindopril if using amlodipine alone caused edema. Perindopril is a long-lasting ACE inhibitor.
- Amlodipine/telmisartan, where telmisartan is an angiotensin II receptor antagonist.
- Amlodipine/valsartan or amlodipine/valsartan/hydrochlorothiazide, where valsartan is an angiotensin II receptor antagonist.
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. 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. 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. 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.
Some common dose-dependent side effects of amolodipine include vasodilatory effects, peripheral edema, dizziness, palpitations, and flushing. 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. 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. Amlodipine-association edema can be avoided by adding ACE inhibitors or angiontensin II receptor antagonist. 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.
Common but not 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%). Side effects occurring less than 1% of the time include: blood disorders, impotence, depression, peripheral neuropathy, insomnia, tachycardia, gingival enlargement, hepatitis, and jaundice.
Although rare, amlodipine overdose toxicity can result in widening of blood vessels, severe low blood pressure, and fast heart rate. Toxicity is generally managed with fluid replacement 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.
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. 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). When more than 20 mg of simvastatin, a lipid-lowering agent, are given with amlodipine, the risk of myopathy increases. Giving amlodipine with Viagra increases the risk of hypotension.
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.
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. 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.
The mechanisms by which amlodipine relieves angina are:
- Stable 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.
- Variant angina: amlodipine blocks spasm of the coronary arteries and restores 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.
Amlodipine has been studied in healthy volunteers following oral administration of 14C-labelled drug. 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. 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. 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.
Pfizer's patent protection on Norvasc lasted until 2007; total patent expiration occurred later in 2007. 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.
Amlodipine is most often used to treat systemic hypertension in cats and dogs. In cats, it is the first line of treatment due to its efficacy and few side effects. 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. 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. By decreasing resistance to forward flow in the systemic circulation it results in a decrease in regurgitant flow into the left atrium. 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.
- "Medical Definition of AMLODIPINE". www.merriam-webster.com. Archived from the original on 8 November 2016. Retrieved 5 July 2017.
- "Norvasc Prescribing Information" (PDF). Archived (PDF) from the original on 16 February 2017. Retrieved 3 July 2017.
- "Amlodipine Besylate". Drugs.com. American Society of Hospital Pharmacists. Archived from the original on 4 June 2016. Retrieved 22 July 2016.
- The ESC Textbook of Preventive Cardiology: Clinical Practice. Oxford University Press. 2015. p. 261. ISBN 9780199656653.
- Chorghade, Mukund S. (2006). Drug Discovery and Development. 1. Hoboken: John Wiley & Sons. p. 207. ISBN 9780471780090. Archived from the original on 15 August 2016.
- "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
- "Amlodipine". International Drug Price Indicator Guide. Archived from the original on 11 August 2017. Retrieved 23 July 2016.
- Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia (Deluxe Lab-Coat ed.). Jones & Bartlett Learning. p. 154. ISBN 9781284057560.
- 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.
- MedlinePlus Encyclopedia Stable angina
- 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.
- "Amlodipine besylate tablet". DailyMed. US National Library of Medicine. Archived from the original on 29 October 2015. Retrieved 5 November 2015.
- "Amlodipine Disease Interactions". Drugs.com. Archived from the original on 11 August 2017. Retrieved 4 July 2017.
- 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.
- 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.
- "Amlodipine 5mg Tablets". emc. 30 May 2017. Archived from the original on 14 July 2017. Retrieved 3 July 2017.
- Russell, R. P. (1988). "Side effects of calcium channel blockers" (PDF). Hypertension. 11 (3 Pt 2): II42–4. doi:10.1161/01.HYP.11.3_Pt_2.II42. ISSN 0194-911X. PMID 3280492. Archived (PDF) from the original on 11 August 2017.
- 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.
- 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.
- 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.
- Aronson, J (2014). Side Effects of Drugs Annual 35. Elsevier. ISBN 978-0-444-62635-6.
- Pillay, V (2013). Modern Medical Toxicology (4th ed.). Jaypee. ISBN 978-93-5025-965-8.
- Hui, David (2015). Approach to Internal Medicine: A Resource Book for Clinical Practice (4th ed.). Springer. ISBN 978-3-319-11820-8.
- 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.
- 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.
- 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 (PDF) from the original on 1 July 2016.
- 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.
- 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.
- 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.
- Learning, Jones; Learning, Bartlett (2012). 2013 Nurse's Drug Handbook. Jones & Bartlett Publishers. ISBN 9781449642846. Archived from the original on 8 September 2017.
- 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.
- 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.
- 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.
- Nayler, Winifred G. (2012). Amlodipine. Springer Science & Business Media. p. 105. ISBN 9783642782237. Archived from the original on 8 September 2017.
- Brittain, Harry G. (2012). Profiles of Drug Substances, Excipients and Related Methodology. Academic Press. ISBN 9780123977564. Archived from the original on 8 September 2017.
- Kennedy VB (22 March 2007). "Pfizer loses court ruling on Norvasc patent". MarketWatch. Archived from the original on 3 August 2008.
- 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.
- Campbell, Anthony K. Intracellular Calcium. John Wiley & Sons. p. 68. ISBN 9781118675526.
- Papich, Mark G. (2007). "Amlodipine Besylate". Saunders Handbook of Veterinary Drugs (2nd ed.). St. Louis, Mo: Saunders/Elsevier. pp. 26–27. ISBN 9781416028888.
- 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.
- Diamondback Drugs. "Amlodipine in Veterinary Medicine". Archived from the original on 11 August 2017. Retrieved 29 June 2017.
- 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.
- 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.
- Forney, Barbara. "Amlodipine for Veterinary Use". Wedgewood Pharmacy. Archived from the original on 27 June 2017. Retrieved 29 June 2017.