Lercanidipine

Lercanidipine is used for the treatment of essential hypertension (high blood pressure).{{cite book|title=Austria-Codex| veditors = Haberfeld H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2015|language=de}}{{cite book|title=Arzneistoff-Profile| veditors = Dinnendahl V, Fricke U |publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|date=2015|edition=28|volume=6|isbn=978-3-7741-9846-3|language=de}}

Lercanidipine seems to be a good agent in treating hypertensive patients that also have kidney issues.{{cite journal | vauthors = Grassi G, Robles NR, Seravalle G, Fici F | title = Lercanidipine in the Management of Hypertension: An Update | journal = Journal of Pharmacology & Pharmacotherapeutics | volume = 8 | issue = 4 | pages = 155–165 | date = 2017 | pmid = 29472747 | pmc = 5820745 | doi = 10.4103/jpp.JPP_34_17 | doi-access = free }}

Like other dihydropyridines, lercanidipine is contraindicated in unstable angina pectoris, uncontrolled cardiac failure, shortly after a myocardial infarction, and in patients with left ventricular outflow tract obstruction. It is also contraindicated during pregnancy and in women who may become pregnant, because data regarding safety for the unborn are lacking, as well as in patients with severe liver and renal impairment.

The drug must not be combined with strong inhibitors of the liver enzyme CYP3A4 or with the immunosuppressant drug ciclosporin.

Lercanidipine is generally well tolerated; no single adverse effect has been observed in more than 1% of patients treated with this drug. Typical side effects are similar to those of other drugs of this class and include headache, dizziness, tachycardia (fast heartbeat), palpitations, flush, and oedema. Hypersensitivity reactions occur in less than one patient in 10,000.

Oedemas are significantly less common under lercanidipine when compared to first-generation dihydropyridines such as nifedipine. For other side effects, data are inconclusive: A study comparing lercanidipine to first-generation drugs found no difference in the frequency of headache and flush,{{cite journal | vauthors = Makarounas-Kirchmann K, Glover-Koudounas S, Ferrari P | title = Results of a meta-analysis comparing the tolerability of lercanidipine and other dihydropyridine calcium channel blockers | journal = Clinical Therapeutics | volume = 31 | issue = 8 | pages = 1652–1663 | date = August 2009 | pmid = 19808126 | doi = 10.1016/j.clinthera.2009.08.010 | s2cid = 42580226 }} but switching from amlodipine, felodipine or nitrendipine (all at least second generation) to lercanidipine significantly decreased side effects in another study.

Overdosing of up to 80 times the usual therapeutic dose has been described. Expected symptoms include severe hypotension (low blood pressure) and reflex tachycardia. Bradycardia (slow heartbeat) can also occur due to blockage of calcium channels in the atrioventricular node of the heart. There is no treatment besides monitoring blood pressure and heart function. Dialysis is likely ineffective because most of the lercanidipine is bound to blood plasma proteins and lipid membranes of cells.

The substance is metabolised by the liver enzyme CYP3A4. In a study, the strong CYP3A4 inhibitor ketoconazole increased the maximal blood plasma concentrations of lercanidipine by a factor of eight, and the area under the curve by a factor of 15. In another study, ciclosporin increased lercanidipine plasma levels threefold when given at the same time. Other inhibitors of this enzyme, such as itraconazole, erythromycin, and grapefruit juice, are also expected to increase plasma concentrations and thus amplify the antihypertensive effect.{{cite journal | vauthors = Klotz U | title = Interaction potential of lercanidipine, a new vasoselective dihydropyridine calcium antagonist | journal = Arzneimittel-Forschung | volume = 52 | issue = 3 | pages = 155–161 | year = 2002 | pmid = 11963641 | doi = 10.1055/s-0031-1299873 | s2cid = 38892707 }} Conversely, CYP3A4 inductors such as carbamazepine, rifampicin, and St John's wort probably lower plasma levels and effectiveness of lercanidipine. By comparison, amlodipine has a lower potential for CYP3A4 mediated interactions.{{cite journal | vauthors = Vincent J, Harris SI, Foulds G, Dogolo LC, Willavize S, Friedman HL | title = Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine | journal = British Journal of Clinical Pharmacology | volume = 50 | issue = 5 | pages = 455–463 | date = November 2000 | pmid = 11069440 | pmc = 2014412 | doi = 10.1046/j.1365-2125.2000.00283.x }}

Lercanidipine increases plasma levels of ciclosporin and digoxin.

Like other dihydropyridine class calcium channel blockers, lercanidipine blocks L-type calcium channels in the smooth muscle cells of blood vessels, relaxing them and thus lowering blood pressure. In contrast to the non-dihydropyridine calcium channel blockers verapamil and diltiazem, it does not significantly act on calcium channels in the atrioventricular node, and therefore does not decrease heart rate, in usual therapeutic doses.

Lercanidipine is slowly but completely absorbed from the gut. It has a total bioavailability of 10% due to an extensive first-pass effect, or up to 40% if taken after a fatty meal. Highest blood plasma levels are reached after 1.5 to 3 hours. The substance is quickly distributed into the tissues and bound to lipid membranes, where it forms a depot. The circulating fraction is almost completely (>98%) bound to plasma proteins.

It is completely metabolized in the liver, mainly via CYP3A4. Elimination half-life is 8 to 10 hours, and the drug does not accumulate. Because of the depot effect, the antihypertensive action lasts for at least 24 hours. 50% is excreted via the urine.

Lercanidipine is used in form of the hydrochloride, which is a slightly yellow crystalline powder and melts at {{convert|197 to 201|C|F}} in crystal form I or {{convert|207 to 211|C|F}} in crystal form II.{{cite patent | country = US | number = 6852737 | title = Crude and crystalline forms of lercanidipine hydrochloride | assign1 = Recordati Ireland Ltd | inventor = Bonifacio F, Campana F, De Iasi G, Leonardi A | gdate = 8 February 2005 | postscript = . }} It is readily soluble in chloroform and methanol, but practically insoluble in water.{{cite web|url=http://www.medsafe.govt.nz/profs/datasheet/z/Zanidiptab.pdf|publisher=Medsafe|title=Zanidip Data Sheet|access-date=15 July 2016}} This high lipophilicity (compared to older dihydropyridines) is intentional because it causes the substance to bind to lipid membranes, allowing for a longer duration of action.{{cite journal | vauthors = Gasser R, Klein W, Köppel H | title = Lercanidipine, a new third generation Ca-antagonist in the treatment of hypertension. | journal = Journal of Clinical and Basic Cardiology | date = January 1999 | volume = 2 | issue = 2 | pages = 169–174 | url = http://www.kup.at/kup/pdf/57.pdf }}

The lercanidipine molecule has one asymmetric carbon atom. While the S-enantiomer is more effective than the R-enantiomer, marketed formulations contain a 1:1 mixture of both (i.e., the racemate).Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, {{ISBN|978-3-946057-10-9}}, S. 171.

Blood plasma concentrations of lercanidipine can be detected by liquid chromatography–mass spectrometry methods.{{cite journal | vauthors = Chen K, Zhang J, Liu S, Zhang D, Teng Y, Wei C, Wang B, Liu X, Yuan G, Zhang R, Zhao W, Guo R | display-authors = 6 | title = Simultaneous determination of lercanidipine, benazepril and benazeprilat in plasma by LC-MS/MS and its application to a toxicokinetics study | journal = Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences | volume = 899 | pages = 1–7 | date = June 2012 | pmid = 22622066 | doi = 10.1016/j.jchromb.2012.04.014 }}

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• {{cite journal | vauthors = Lin TH, Voon WC, Yen HW, Huang CH, Su HM, Lai WT, Sheu SH | title = Lercanidipine and losartan effects on blood pressure and fibrinolytic parameters | journal = The Kaohsiung Journal of Medical Sciences | volume = 22 | issue = 4 | pages = 177–183 | date = April 2006 | pmid = 16679299 | doi = 10.1016/S1607-551X(09)70304-3 | doi-access = free }}
• {{cite journal | vauthors = Martinez ML, Lopes LF, Coelho EB, Nobre F, Rocha JB, Gerlach RF, Tanus-Santos JE | title = Lercanidipine reduces matrix metalloproteinase-9 activity in patients with hypertension | journal = Journal of Cardiovascular Pharmacology | volume = 47 | issue = 1 | pages = 117–122 | date = January 2006 | pmid = 16424795 | doi = 10.1097/01.fjc.0000196241.96759.71 | s2cid = 13406385 | doi-access = free }}
• {{cite journal | vauthors = Agrawal R, Marx A, Haller H | title = Efficacy and safety of lercanidipine versus hydrochlorothiazide as add-on to enalapril in diabetic populations with uncontrolled hypertension | journal = Journal of Hypertension | volume = 24 | issue = 1 | pages = 185–192 | date = January 2006 | pmid = 16331117 | doi = 10.1097/01.hjh.0000198987.34588.11 | s2cid = 3256629 }}

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• {{DiseasesDB|31597}}

{{Calcium channel blockers}}

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Category:Calcium channel blockers

Category:CYP2D6 inhibitors

Category:Dihydropyridines

Category:Carboxylate esters

Category:3-Nitrophenyl compounds

Category:Amines