Lercanidipine: Difference between revisions

{{Short description|Antihypertensive drug of the calcium channel blocker class}}

{{Infobox drug

| verifiedrevid = 408573138

| IUPAC_name = (''RS'')-2[(3,3-Diphenylpropyl)(methyl)amino]-1,1-dimethylethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

| width = 200

<!--Clinical data-->

| tradename = Zanidip, Leridip

| Drugs.com = {{drugs.com|UK|lercanidipine-10mg-film-coated-tablets-leaflet}}

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_US = <!-- A / B / C / D / X -->

| pregnancy_category = C (no data in humans)

| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->

| legal_UK = <!-- GSL / P / POM / CD -->

| legal_US = <!-- OTC / Rx-only -->

| legal_status = Rx-only

| routes_of_administration = [[Mouth|Oral]]

<!--Pharmacokinetic data-->

| bioavailability = ~10% (due to [[first-pass effect]])

| protein_bound = >98%

| metabolism = Mainly [[CYP3A4]]

| onset = <!-- slow -->

| elimination_half-life = 8–10 hours

| duration_of_action = ≥ 24 hours

| excretion = Urine (50%)

<!--Identifiers-->

| CAS_number = 100427-26-7

| CAS_supplemental = <br/>{{CAS|132866-11-6}} ([[hydrochloride|HCl]])

| ATC_prefix = C08

| ATC_suffix = CA13

| ATC_supplemental =

| PubChem = 65866

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00528

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D08111

<!--Chemical data-->

| C=36 | H=41 | N=3 | O=6

| smiles = [O-][N+](=O)c1cccc(c1)C4C(=C(/N\C(=C4\C(=O)OC(C)(C)CN(CCC(c2ccccc2)c3ccccc3)C)C)C)\C(=O)OC

'''Lercanidipine''' (trade name '''Zanidip''', among others) is an [[antihypertensive]] (blood pressure lowering) drug. It belongs to the [[dihydropyridine]] class of [[calcium channel blocker]]s, which work by relaxing and opening the blood vessels allowing the blood to circulate more freely around the body. This lowers the blood pressure and allows the heart to work more efficiently.<ref>{{cite journal | vauthors = Barrios V, Escobar C, Navarro A, Barrios L, Navarro-Cid J, Calderón A | title = Lercanidipine is an effective and well tolerated antihypertensive drug regardless the cardiovascular risk profile: The LAURA study | journal = International Journal of Clinical Practice | volume = 60 | issue = 11 | pages = 1364–1370 | date = November 2006 | pmid = 17073834 | pmc = 1636683 | doi = 10.1111/j.1742-1241.2006.01176.x }}</ref>

The drug acts more slowly than older dihydropyridines.{{citation needed|date=November 2021}} It probably has fewer adverse effects, but a comparatively high potential for drug interactions.

<!-- Society and culture -->

It was patented in 1984 and first approved for medical use in 1997.<ref>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=466 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA466 |language=en}}</ref> The [[US FDA]] refused to approve the drug, and lercanidipine is not marketed in USA.<ref>{{Cite web |title=NCATS Inxight Drugs — LERCANIDIPINE HYDROCHLORIDE |url=https://drugs.ncats.io/drug/OA8TFX68PE |access-date=2024-04-16 |website=drugs.ncats.io |language=en}}</ref>

== Medical uses ==

Lercanidipine is used for the treatment of [[essential hypertension]] (high blood pressure).<ref name="AC">{{cite book|title=Austria-Codex| veditors = Haberfeld H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2015|language=de}}</ref><ref name="Dinnendahl">{{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}}</ref>

Lercanidipine seems to be a good agent in treating hypertensive patients that also have kidney issues.<ref name="pmid29472747">{{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 }}</ref>

== Contraindications ==

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]].<ref name="AC" /><ref name="Dinnendahl" />

The drug must not be combined with strong inhibitors of the liver enzyme [[CYP3A4]] or with the immunosuppressant drug [[ciclosporin]].<ref name="AC" /><ref name="Dinnendahl" />

== Adverse effects ==

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 (physiology)|flush]], and [[oedema]]. [[Hypersensitivity]] reactions occur in less than one patient in 10,000.<ref name="AC" /><ref name="Dinnendahl" />

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,<ref>{{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 }}</ref> but switching from [[amlodipine]], [[felodipine]] or [[nitrendipine]] (all at least second generation) to lercanidipine significantly decreased side effects in another study.<ref name="Dinnendahl" />

== Overdose ==

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. [[Kidney dialysis|Dialysis]] is likely ineffective because most of the lercanidipine is bound to blood [[plasma protein]]s and [[lipid membrane]]s of cells.<ref name="AC" />

== Interactions ==

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 (pharmacokinetics)|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.<ref name="AC" /><ref name="Dinnendahl" /><ref name="Klotz">{{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 }}</ref> Conversely, CYP3A4 inductors such as [[carbamazepine]], [[rifampicin]], and [[St John's wort]] probably lower plasma levels and effectiveness of lercanidipine.<ref name="Dinnendahl" /><ref name="Klotz" /> By comparison, amlodipine has a lower potential for CYP3A4 mediated interactions.<ref name="AC" /><ref>{{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 }}</ref>

Lercanidipine increases plasma levels of ciclosporin and [[digoxin]].<ref name="AC" /><ref name="Dinnendahl" />

== Pharmacology ==

=== Mechanism of action ===

Like other dihydropyridine class calcium channel blockers, lercanidipine blocks [[L-type calcium channel]]s 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.<ref name="Dinnendahl" />

=== Pharmacokinetics ===

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.<ref name="AC" /><ref name="Dinnendahl" />

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.<ref name="AC" /><ref name="Dinnendahl" />

== Chemistry ==

Lercanidipine is used in form of the [[hydrochloride]],<ref name="AC" /> 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.<ref>{{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 = . }}</ref> It is readily soluble in [[chloroform]] and [[methanol]], but practically insoluble in water.<ref>{{cite web|url=http://www.medsafe.govt.nz/profs/datasheet/z/Zanidiptab.pdf|publisher=[[Medsafe]]|title=Zanidip Data Sheet|access-date=15 July 2016}}</ref> 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.<ref>{{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 }}</ref>

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]]).<ref name="Dinnendahl" /><ref name="Rote Liste">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.</ref>

{| class="wikitable" style="text-align:center"

|- class="hintergrundfarbe6"

! colspan="2"| Enantiomers of lercanidipine

|-

| [[File:(R)-Lercanidipin Structural Formula V1.svg|300 px]]<br />(''R'')-lercanidipin<small><br />CAS number: 185197-70-0</small>

| [[File:(S)-Lercanidipin Structural Formula V1.svg|300 px]]<br />(''S'')-lercanidipin<small><br />CAS number: 185197-71-1</small>

|}

=== Detection in body fluids ===

Blood plasma concentrations of lercanidipine can be detected by [[liquid chromatography–mass spectrometry]] methods.<ref>{{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 }}</ref>

== References ==

{{reflist}}

== Further reading ==

{{refbegin}}

* {{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 }}

{{refend}}

== External links ==

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