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a salt or ester of maleic acid; used as a nontricyclic antidepressant drug for psychomotor activation

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/09/06 15:09:12」(JST)

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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 World Health Organization's 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.

Contraindications

Breastfeeding
Cardiogenic shock
Unstable angina
Systolic and diastolic blood pressure below 90/60 mmHg
Aortic stenosis

Adverse effects

Adverse side effects of the use of amlodipine may include:^[5]

Common: peripheral edema and fatigue
Uncommon: blood disorders, development of breasts in men (gynecomastia), impotence, depression, insomnia, tachycardia, or gingival enlargement
Rarely: erratic behavior, hepatitis, jaundice

Mechanism

Amlodipine inhibits 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.^[6] ^[7]

The mechanisms by which amlodipine relieves angina include:

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.^[8]

Prinzmetal's 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.^[9]

Metabolism

Amlodipine has been studied in healthy volunteers following oral administration of ¹⁴C-labelled drug.^[10] 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.^[11]

Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study

The "Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy" (CASTLE) Study gave the result that both the cheap generic Amlodipine and the more expensive Candesartan cilexetil were both effective in the treatment of mild hypertension stage-1 (maximum 160/100 mm Hg) with no significant difference. Amlodipine decreased systolic and diastolic BP by -15.4/-11.3 mm Hg, while Candesartan cilexetil did so by -15.2/-10.2 mm Hg. But the most common side effect was Peripheral edema, which happened with greater frequency using Amlodipine (22.1%; mild 8.7%, moderate 11.8%, and severe 1.6%), while the increase using Candesartan cilexetil was 8.9%; (mild 8.1%, and moderate 0.8%).^[12]

Combination therapy

If monotherapy with Amlodipine or Candesartan is not sufficient to reach the reducing blood pressure target, a combination of Amlodipine 5mg and Candesartan 8mg can be effective, lowering blood pressure after 12 weeks in patients not adequately controlled by monotherapy.^[13]

History

Pfizer's patent protection on Norvasc lasted until 2007; total patent expiration occurred later in 2007.^[14] 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.^[15]

References

^ "Amlodipine: MedlinePlus Drug Information". www.nlm.nih.gov. Retrieved 2015-05-21.
^ Cash, Jill C.; Glass, Cheryl Anne (2014-02-10). Family Practice Guidelines, Third Edition. Springer Publishing Company. ISBN 9780826197825.
^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
^ 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.
^ Munoz, Ricardo; Vetterly, Carol G.; Roth, Stephen J.; Cruz, Eduardo da (2007-10-18). Handbook of Pediatric Cardiovascular Drugs. Springer Science & Business Media. ISBN 9781846289538.
^ Arcangelo, Virginia Poole; Peterson, Andrew M. (2006). Pharmacotherapeutics for Advanced Practice: A Practical Approach. Lippincott Williams & Wilkins. ISBN 9780781757843.
^ Ritter, James; Lewis, Lionel; Mant, Timothy; Ferro, Albert (2012-12-11). A Textbook of Clinical Pharmacology and Therapeutics, 5Ed. CRC Press. ISBN 9781444113006.
^ Li, Y. Robert (2015-04-06). Cardiovascular Diseases: From Molecular Pharmacology to Evidence-Based Therapeutics. John Wiley & Sons. ISBN 9780470915370.
^ LEARNING, JONES & BARTLETT; Bartlett, Jones and (2012-07-15). 2013 Nurse's Drug Handbook. Jones & Bartlett Publishers. ISBN 9781449642846.
^ 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.
^ Brittain, Harry G. (2012-05-09). Profiles of Drug Substances, Excipients and Related Methodology. Academic Press. ISBN 9780123977564.
^ AM J Cardiol. "Comparative effects of candesartan cilexetil and amlodipine in patients with mild systemic hypertension. Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study Investigators". Retrieved June 22, 2015.
^ Kazuaki Nishio, Takeshi Kondo, Youichi Kobayashi. "Efficacy and Tolerability of Candesartan Cilexetil and Amlodipine in Patients with Poorly Controlled Essential Hypertension". Retrieved July 21, 2015.
^ Kennedy VB (22 March 2007). "Pfizer loses court ruling on Norvasc patent". MarketWatch.
^ 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

U.S. National Library of Medicine: Drug Information Portal - Amlodipine

UpToDate Contents

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1. 無症候性腹部大動脈瘤のマネージメント management of asymptomatic abdominal aortic aneurysm
2. 収縮機能障害による心不全におけるカルシウム拮抗剤 calcium channel blockers in heart failure due to systolic dysfunction
3. 原発性（本態性）高血圧における治療選択：推奨 choice of therapy in primary essential hypertension recommendations
4. 安定狭心症のマネージメントにおけるカルシウム拮抗剤 calcium channel blockers in the management of stable angina pectoris
5. 原発性（本態性）高血圧における治療選択：臨床試験 choice of therapy in primary essential hypertension clinical trials

English Journal

The impact of chirality on the development of robust and stable tablet formulation of (S-) amlodipine besylate.

Hadžidedić S1, Uzunović A, Sehić Jazić S, Kocova El-Arini S.Author information 1Agency for Medicinal Products and Medical Devices of B&H , Sarajevo , Bosnia and Herzegovina .AbstractThe aim of this study was to compare the specific characteristics of the S-enantiomer and the racemate of amlodipine besylate (AB) in order to design a robust and stable formulation of the active S-enantiomer which will guarantee continuous performance of the unichiral version of amlodipine. Preformulation studies showed that the S-enantiomer and the racemate exhibit different crystal morphology, particle size distribution and higroscopicity. The S-enantiomer exhibited significantly lower melting temperature compared to the racemate which was in accordance with its higher water solubility and its increased intrinsic dissolution rate. The thermograms of S-amlodipine besylate indicated that dehydration and melting occur at almost the same time and the dehydration event overlaps with the melting peak. Forced degradation tests conducted on both substances showed high levels of degradation into amlodipine related substance D as well as other impurities. Tablets prepared with S-AB, simulating originator's formulation, failed in stability tests due to drug incompatibility with calcium hydrogen phosphate. Therefore, a tablet formulation based on excipients which were confirmed compatible with S-AB was developed and optimized using full factorial design to obtain a dissolution profile comparative to the brand product. Stability studies conducted at 40 °C/75% relative humidity (RH) confirmed that appearance, drug content and drug release of the optimized tablet formulation remained within the recommended limits.
Pharmaceutical development and technology.Pharm Dev Technol.2014 Dec;19(8):930-41. doi: 10.3109/10837450.2013.840847. Epub 2013 Oct 7.
The aim of this study was to compare the specific characteristics of the S-enantiomer and the racemate of amlodipine besylate (AB) in order to design a robust and stable formulation of the active S-enantiomer which will guarantee continuous performance of the unichiral version of amlodipine. Preform
PMID 24099553

Spectrophotometric methods for simultaneous determination of ternary mixture of amlodipine besylate, olmesartan medoxomil and hydrochlorothiazide.

Merey HA1, Ramadan NK1, Diab SS2, Moustafa AA1.Author information 1Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El Aini Post, 11562 Cairo, Egypt.2Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El Aini Post, 11562 Cairo, Egypt. Electronic address: sherinediab@yahoo.com.AbstractFour, accurate, precise, and sensitive spectrophotometric methods are developed for the simultaneous determination of a ternary mixture containing amlodipine besylate (AM), olmesartan medoxomil (OL) and hydrochlorothiazide (HZ), where AM is determined at its λmax 364.6nm ((0)D), while (OL) and (HZ) are determined by different methods. Method (A) depends on determining OL and HZ by measuring the second derivative of the ratio spectra ((2)DD) at 254.4 and 338.6nm, respectively. Method (B) is first derivative of the double divisor ratio spectra (D-(1)DD) at 260.4 and 273.0nm for OL and HZ, respectively. Method (C) based on successive spectrophotometric resolution technique (SSRT). The technique starts with the ratio subtraction method then measuring OL and HZ at their isoabsorptive point at 260.0nm, while HZ is measured using the amplitude of first derivative at 335.2nm. Method (D) is mean centering of the ratio spectra (MCR) at 252.0nm and 220.0nm for OL and HZ, respectively. The specificity of the developed methods is investigated by analyzing laboratory prepared mixtures containing different ratios of the three drugs and their combined dosage form. The obtained results are statistically compared with those obtained by the official or reported methods, showing no significant difference with respect to accuracy and precision at p=0.05.
Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.Spectrochim Acta A Mol Biomol Spectrosc.2014 May 5;125:138-46. doi: 10.1016/j.saa.2014.01.095. Epub 2014 Jan 30.
Four, accurate, precise, and sensitive spectrophotometric methods are developed for the simultaneous determination of a ternary mixture containing amlodipine besylate (AM), olmesartan medoxomil (OL) and hydrochlorothiazide (HZ), where AM is determined at its λmax 364.6nm ((0)D), while (OL) and (HZ)
PMID 24534425

Broad-spectrum antiemetic efficacy of the l-type calcium channel blocker amlodipine in the least shrew (Cryptotis parva).

Zhong W1, Chebolu S1, Darmani NA2.Author information 1Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766, USA.2Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766, USA. Electronic address: ndarmani@westernu.edu.AbstractThe dihydropyridine l-type calcium (Ca(2+)) channel blockers nifedipine and amlodipine reduce extracellular Ca(2+) entry into cells. They are widely used for the treatment of hypertensive disorders. We have recently demonstrated that extracellular Ca(2+) entry via l-type Ca(2+) channels is involved in emesis and that nifedipine has broad-spectrum antiemetic activity. The aim of this study was to evaluate the antiemetic efficacy of the longer-acting l-type Ca(2+) channel blocker, amlodipine. Fully effective emetic doses of diverse emetogens such as the l-type Ca(2+) channel agonist (FPL 64176) as well as selective and/or nonselective agonists of serotonergic 5-HT3 (e.g. 5-HT or 2-Me-5-HT)-, dopamine D2 (e.g. apomorphine or quinpirole)-, cholinergic M1 (e.g. pilocarpine or McN-A343)- and tachykininergic NK1 (e.g. GR73632)-receptors, were administered intraperitoneally (i.p.) in the least shrew to induce vomiting. The broad-spectrum antiemetic potential of amlodipine was evaluated against these emetogens. Subcutaneous (s.c.) administration of amlodipine (0.5-10mg/kg) attenuated in a dose-dependent and potent manner both the frequency and percentage of shrews vomiting in response to intraperitoneal (i.p.) administration of FPL 64176 (10mg/kg), 5-HT (5mg/kg), 2-Me-5-HT (5mg/kg), apomorphine (2mg/kg), quinpirole (2mg/kg), pilocarpine (2mg/kg), McN-A343 (2mg/kg), or GR73632 (5mg/kg). A combination of non-effective doses of amlodipine (0.5mg/kg, s.c.) and the 5-HT3 receptor antagonist palonosetron (0.05mg/kg, s.c.) was more effective against FPL 64176-induced vomiting than their corresponding doses tested alone. Amlodipine by itself suppressed the frequency of acute cisplatin (10mg/kg, i.p)-induced vomiting in a dose-dependent manner. Moreover, a combination of a non-effective dose of amlodipine (1mg/kg) potentiated the antiemetic efficacy of a semi-effective dose of palonosetron (0.5mg/kg, s.c.) against acute vomiting caused by cisplatin. We confirm that influx of extracellular Ca(2±) ion underlies vomiting due to diverse causes and demonstrate that l-type Ca(2+) channel blockers are a new class of broad-spectrum antiemetics.
Pharmacology, biochemistry, and behavior.Pharmacol Biochem Behav.2014 May;120:124-32. doi: 10.1016/j.pbb.2014.03.005. Epub 2014 Mar 12.
The dihydropyridine l-type calcium (Ca(2+)) channel blockers nifedipine and amlodipine reduce extracellular Ca(2+) entry into cells. They are widely used for the treatment of hypertensive disorders. We have recently demonstrated that extracellular Ca(2+) entry via l-type Ca(2+) channels is involved
PMID 24631485

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リンク元	「amlodipine besylate」
関連記事	「maleate」

「amlodipine besylate」

Amlodipine
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
Trade names	Norvasc
AHFS/Drugs.com	monograph
MedlinePlus	a692044
Licence data	US FDA:link
Pregnancy; category	AU: C; US: C (Risk not ruled out);
Legal status	UK: Prescription-only (POM); US: ℞-only;
Routes of; administration	Oral (tablets)
Pharmacokinetic data
Bioavailability	64 to 90%
Metabolism	Hepatic
Biological half-life	30 to 50 hours
Excretion	Renal
Identifiers
CAS Registry Number	88150-42-9
ATC code	C08CA01
PubChem	CID: 2162
IUPHAR/BPS	6981
DrugBank	DB00381
ChemSpider	2077
UNII	1J444QC288
KEGG	D07450
ChEBI	CHEBI:2668
ChEMBL	CHEMBL1491
Chemical data
Formula	C20H25ClN2O5
Molecular mass	408.879 g/mol
	SMILES Clc1ccccc1C2C(=C(/N/C(=C2/C(=O)OCC)COCCN)C)\C(=O)OC ;
	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 ; Key:HTIQEAQVCYTUBX-UHFFFAOYSA-N ;
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