Lercanidipine

Last updated
Lercanidipine
Lercanidipine.svg
Clinical data
Trade names Zanidip, Leridip
AHFS/Drugs.com UK Drug Information
Pregnancy
category
  • C (no data in humans)
Routes of
administration 		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability ~10% (due to first-pass effect)
Protein binding >98%
Metabolism Mainly CYP3A4
Elimination half-life 8–10 hours
Duration of action ≥ 24 hours
Excretion Urine (50%)
Identifiers
  • (RS)-2[(3,3-Diphenylpropyl)(methyl)amino]-1,1-dimethylethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.235.079 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C36H41N3O6
Molar mass 611.739 g·mol−1
3D model (JSmol)
  • [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
  • InChI=1S/C36H41N3O6/c1-24-31(34(40)44-6)33(28-18-13-19-29(22-28)39(42)43)32(25(2)37-24)35(41)45-36(3,4)23-38(5)21-20-30(26-14-9-7-10-15-26)27-16-11-8-12-17-27/h7-19,22,30,33,37H,20-21,23H2,1-6H3 Yes check.svgY
  • Key:ZDXUKAKRHYTAKV-UHFFFAOYSA-N Yes check.svgY
   (verify)

Lercanidipine (trade name Zanidip, among others) is an antihypertensive (blood pressure lowering) drug. It belongs to the dihydropyridine class of calcium channel blockers, 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. [1]

Contents

The drug acts more slowly than older dihydropyridines.[ citation needed ] It probably has fewer adverse effects, but a comparatively high potential for drug interactions.

It was patented in 1984 and first approved for medical use in 1997. [2] The US FDA refused to approve the drug, and lercanidipine is not marketed in USA. [3]

Medical uses

Lercanidipine is used for the treatment of essential hypertension (high blood pressure). [4] [5]

Lercanidipine seems to be a good agent in treating hypertensive patients that also have kidney issues. [6]

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. [4] [5]

The drug must not be combined with strong inhibitors of the liver enzyme CYP3A4 or with the immunosuppressant drug ciclosporin. [4] [5]

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, and oedema. Hypersensitivity reactions occur in less than one patient in 10,000. [4] [5]

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, [7] but switching from amlodipine, felodipine or nitrendipine (all at least second generation) to lercanidipine significantly decreased side effects in another study. [5]

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. Dialysis is likely ineffective because most of the lercanidipine is bound to blood plasma proteins and lipid membranes of cells. [4]

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 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. [4] [5] [8] Conversely, CYP3A4 inductors such as carbamazepine, rifampicin, and St John's wort probably lower plasma levels and effectiveness of lercanidipine. [5] [8] By comparison, amlodipine has a lower potential for CYP3A4 mediated interactions. [4] [9]

Lercanidipine increases plasma levels of ciclosporin and digoxin. [4] [5]

Pharmacology

Mechanism of action

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. [5]

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. [4] [5]

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. [4] [5]

Chemistry

Lercanidipine is used in form of the hydrochloride, [4] which is a slightly yellow crystalline powder and melts at 197 to 201 °C (387 to 394 °F) in crystal form I or 207 to 211 °C (405 to 412 °F) in crystal form II. [10] It is readily soluble in chloroform and methanol, but practically insoluble in water. [11] 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. [12]

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). [5] [13]

Enantiomers of lercanidipine
(R)-Lercanidipin Structural Formula V1.svg
(R)-lercanidipin
CAS number: 185197-70-0		 (S)-Lercanidipin Structural Formula V1.svg
(S)-lercanidipin
CAS number: 185197-71-1

Detection in body fluids

Blood plasma concentrations of lercanidipine can be detected by liquid chromatography–mass spectrometry methods. [14]

Related Research Articles

Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are also frequently used to alter heart rate, to prevent peripheral and cerebral vasospasm, and to reduce chest pain caused by angina pectoris.

<span class="mw-page-title-main">Verapamil</span> Calcium channel blocker medication

Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina, and supraventricular tachycardia. It may also be used for the prevention of migraines and cluster headaches. It is given by mouth or by injection into a vein.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Amlodipine</span> Medication against high blood pressure

Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat high blood pressure, coronary artery disease (CAD) and variant angina. It is taken orally.

<span class="mw-page-title-main">Diltiazem</span> Calcium channel blocker medication

Diltiazem, sold under the brand name Cardizem among others, is a nondihydropyridine calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used. It is taken by mouth or injection into a vein. When given by injection, effects typically begin within a few minutes and last a few hours.

<span class="mw-page-title-main">Indapamide</span> Thiazide-like diuretic drug

Indapamide is a thiazide-like diuretic drug used in the treatment of hypertension, as well as decompensated heart failure. Combination preparations with perindopril are available. The thiazide-like diuretics reduce risk of major cardiovascular events and heart failure in hypertensive patients compared with hydrochlorothiazide with a comparable incidence of adverse events. Both thiazide diuretics and thiazide-like diuretics are effective in reducing risk of stroke. Both drug classes appear to have comparable rates of adverse effects as other antihypertensives such as angiotensin II receptor blockers and dihydropyridine calcium channel blockers and lesser prevalence of side-effects when compared to ACE-inhibitors and non-dihydropyridine calcium channel blockers.

<span class="mw-page-title-main">Felodipine</span> Medication of the calcium channel blocker type

Felodipine is a medication of the calcium channel blocker type that is used to treat high blood pressure.

<span class="mw-page-title-main">Nimodipine</span> Antihypertensive drug of the calcium channel blocker class

Nimodipine, sold under the brand name Nimotop among others, is a calcium channel blocker used in preventing vasospasm secondary to subarachnoid hemorrhage. It was originally developed within the calcium channel blocker class as it was used for the treatment of high blood pressure, but is not used for this indication.

Alpha-1 blockers constitute a variety of drugs that block the effect of catecholamines on alpha-1-adrenergic receptors. They are mainly used to treat benign prostatic hyperplasia (BPH), hypertension and post-traumatic stress disorder. Alpha-1 adrenergic receptors are present in vascular smooth muscle, the central nervous system, and other tissues. When alpha blockers bind to these receptors in vascular smooth muscle, they cause vasodilation.

<span class="mw-page-title-main">Perindopril</span> High blood pressure medication

Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease.

<span class="mw-page-title-main">Nebivolol</span> Chemical compound

Nebivolol is a beta blocker used to treat high blood pressure and heart failure. As with other β-blockers, it is generally a less preferred treatment for high blood pressure. It may be used by itself or with other blood pressure medication. It is taken by mouth.

<span class="mw-page-title-main">Isradipine</span> Antihypertensive drug of the calcium channel blocker class

Isradipine is a calcium channel blocker of the dihydropyridine class. It is usually prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack.

<span class="mw-page-title-main">Nisoldipine</span> Antihypertensive drug of the calcium channel blocker class

Nisoldipine is a pharmaceutical drug used for the treatment of chronic angina pectoris and hypertension. It is a calcium channel blocker of the dihydropyridine class. It is sold in the United States under the proprietary name Sular. Nisoldipine has tropism for cardiac blood vessels.

<span class="mw-page-title-main">Nitrendipine</span> Antihypertensive drug of the calcium channel blocker class

Nitrendipine is a dihydropyridine calcium channel blocker. It is used in the treatment of primary (essential) hypertension to decrease blood pressure and can reduce the cardiotoxicity of cocaine.

<span class="mw-page-title-main">Clevidipine</span> Antihypertensive drug of the calcium channel blocker class

Clevidipine is a dihydropyridine calcium channel blocker indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. Clevidipine is used IV only and practitioners titrate this drug to lower blood pressure. It has a half-life of approximately one minute. It is rapidly inactivated by esterases.

<span class="mw-page-title-main">Manidipine</span> Antihypertensive drug of the calcium channel blocker class

Manidipine is a calcium channel blocker that is used clinically as an antihypertensive.

<span class="mw-page-title-main">Cilnidipine</span> Antihypertensive drug of the calcium channel blocker class

Cilnidipine is a calcium channel blocker. Cilnidipine is approved for use in Japan, China, India, Nepal, and Korea for hypertension.

<span class="mw-page-title-main">Efonidipine</span> Antihypertensive drug of the calcium channel blocker class

Efonidipine (INN) is a dihydropyridine calcium channel blocker marketed by Shionogi & Co. of Japan. It was launched in 1995, under the brand name Landel (ランデル). The drug blocks both T-type and L-type calcium channels. Drug Controller General of India (DCGI) has approved the use of efonidipine in India. It is launched under the brand name "Efnocar".

<span class="mw-page-title-main">Levamlodipine</span> Chemical compound

Levamlodipine (INN), also known as levoamlodipine or S-amlodipine is a pharmacologically active enantiomer of amlodipine. Amlodipine belongs to the dihydropyridine group of calcium channel blocker used as an antihypertensive and antianginal agent. It was approved by the U.S. FDA in December 2019 and is currently marketed under the brand name Conjupri.

<span class="mw-page-title-main">Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial</span>

The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial, also known as ALLHAT, was a randomized, double-blind, active-controlled study comparing at the same time, four different classes of antihypertensive drugs with the rate of coronary heart disease (CHD) events in ‘high-risk’ people with hypertension. Participants were initially randomised to chlorthalidone (diuretic) versus doxazosin, lisinopril (ACE-inhibitor), and amlodipine.

References

  1. ↑ Barrios V, Escobar C, Navarro A, Barrios L, Navarro-Cid J, Calderón A (November 2006). "Lercanidipine is an effective and well tolerated antihypertensive drug regardless the cardiovascular risk profile: The LAURA study". International Journal of Clinical Practice. 60 (11): 1364–1370. doi:10.1111/j.1742-1241.2006.01176.x. PMC   1636683 . PMID   17073834.
  2. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 466. ISBN   9783527607495.
  3. ↑ "NCATS Inxight Drugs — LERCANIDIPINE HYDROCHLORIDE". drugs.ncats.io. Retrieved 2024-04-16.
  4. 1 2 3 4 5 6 7 8 9 10 11 Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 Dinnendahl V, Fricke U, eds. (2015). Arzneistoff-Profile (in German). Vol. 6 (28 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN   978-3-7741-9846-3.
  6. ↑ Grassi G, Robles NR, Seravalle G, Fici F (2017). "Lercanidipine in the Management of Hypertension: An Update". Journal of Pharmacology & Pharmacotherapeutics. 8 (4): 155–165. doi: 10.4103/jpp.JPP_34_17 . PMC   5820745 . PMID   29472747.
  7. ↑ Makarounas-Kirchmann K, Glover-Koudounas S, Ferrari P (August 2009). "Results of a meta-analysis comparing the tolerability of lercanidipine and other dihydropyridine calcium channel blockers". Clinical Therapeutics. 31 (8): 1652–1663. doi:10.1016/j.clinthera.2009.08.010. PMID   19808126. S2CID   42580226.
  8. 1 2 Klotz U (2002). "Interaction potential of lercanidipine, a new vasoselective dihydropyridine calcium antagonist". Arzneimittel-Forschung. 52 (3): 155–161. doi:10.1055/s-0031-1299873. PMID   11963641. S2CID   38892707.
  9. ↑ Vincent J, Harris SI, Foulds G, Dogolo LC, Willavize S, Friedman HL (November 2000). "Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine". British Journal of Clinical Pharmacology. 50 (5): 455–463. doi:10.1046/j.1365-2125.2000.00283.x. PMC   2014412 . PMID   11069440.
  10. ↑ US 6852737,Bonifacio F, Campana F, De Iasi G, Leonardi A,"Crude and crystalline forms of lercanidipine hydrochloride",issued 8 February 2005, assigned to Recordati Ireland Ltd.
  11. ↑ "Zanidip Data Sheet" (PDF). Medsafe . Retrieved 15 July 2016.
  12. ↑ Gasser R, Klein W, Köppel H (January 1999). "Lercanidipine, a new third generation Ca-antagonist in the treatment of hypertension" (PDF). Journal of Clinical and Basic Cardiology. 2 (2): 169–174.
  13. ↑ 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.
  14. ↑ Chen K, Zhang J, Liu S, Zhang D, Teng Y, Wei C, et al. (June 2012). "Simultaneous determination of lercanidipine, benazepril and benazeprilat in plasma by LC-MS/MS and its application to a toxicokinetics study". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 899: 1–7. doi:10.1016/j.jchromb.2012.04.014. PMID   22622066.

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