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Identification
Name Isradipine
Accession Number DB00270 (APRD00298)
Type small molecule
Groups approved
Description

Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. It is structurally related to felodipine, nifedipine, and nimodipine and is the most potent calcium-channel blocking agent of the DHP class. Isradipine binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and arterial smooth muscle cells. It exhibits greater selectivity towards arterial smooth muscle cells owing to alternative splicing of the alpha-1 subunit of the channel and increased prevalence of inactive channels in smooth muscle cells. Isradipine may be used to treat mild to moderate essential hypertension.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
(+/-)-Isradipine
Isradipin
Isradipino [Spanish]
Isradipinum [Latin]
Isrodipine
Salts Not Available
Brand names
Name Company
Clivoten Italfarmaco (Italy)
DynaCirc Novartis (Hong Kong, Malaysia, Mexico, New Zealand, South Africa, Singapore, Thailand, Turkey, United States)
Dynacirc CR Reliant, GlaxoSmithKline
DynaCire
DynaCire CR
Dynacrine
Esradin Sigma-Tau (Italy)
Lomir Novartis (Austria, Brazil, Czech Republic, Denmark, Finland, Germany, Greece, Hungary, Netherlands, Norway, Poland, Russia, Sweden), Sankyo (Belgium, Italy), Daiichi Sankyo (Portugal, Switzerland), Mizar (Spain)
Prescal Novartis (United Kingdom)
Rebriden
Brand mixtures Not Available
Categories
  • Antihypertensive Agents
  • Vasodilator Agents
  • Calcium Channel Blockers
CAS number 75695-93-1
Weight Average: 371.3871
Monoisotopic: 371.148120797
Chemical Formula C19H21N3O5
InChI Key InChIKey=HMJIYCCIJYRONP-UHFFFAOYSA-N
InChI
InChI=1S/C19H21N3O5/c1-9(2)26-19(24)15-11(4)20-10(3)14(18(23)25-5)16(15)12-7-6-8-13-17(12)22-27-21-13/h6-9,16,20H,1-5H3
Plain Text
IUPAC Name
3-methyl 5-propan-2-yl 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
SMILES
COC(=O)C1=C(C)NC(C)=C(C1C1=CC=CC2=NON=C12)C(=O)OC(C)C
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Dihydropyridines
  • Carboxylic Acids and Derivatives
  • Benzene and Derivatives
Substructures
  • Dihydropyridines
  • Carboxylic Acids and Derivatives
  • Acetates
  • Ethers
  • Benzene and Derivatives
  • Enamines
  • Heterocyclic compounds
  • Aromatic compounds
Pharmacology
Indication For the management of mild to moderate essential hypertension. It may be used alone or concurrently with thiazide-type diuretics.
Pharmacodynamics Isradipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of isradipine result in an overall decrease in blood pressure.
Mechanism of action Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, isradipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives isradipine additional arterial selectivity. At therapeutic sub-toxic concentrations, isradipine has little effect on cardiac myocytes and conduction cells.
Absorption Isradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%.
Volume of distribution Not Available
Protein binding 95%
Metabolism
Hepatic. Completely metabolized prior to excretion and no unchanged drug is detected in the urine.
Route of elimination Approximately 60% to 65% of an administered dose is excreted in the urine and 25% to 30% in the feces.
Half life 8 hours
Clearance Not Available
Toxicity Symptoms of overdose include lethargy, sinus tachycardia, and transient hypotension. Significant lethality was observed in mice given oral doses of over 200 mg/kg and rabbits given about 50 mg/kg of isradipine. Rats tolerated doses of over 2000 mg/kg without effects on survival.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00378 Isradipine Pathway SMP00378
Pharmacoeconomics
Manufacturers
  • Smithkline beecham corp dba glaxosmithkline
  • Actavis totowa llc
  • Watson laboratories inc
  • Glaxosmithkline llc
Packagers
Dosage forms
Form Route Strength
Capsule Oral 2.5 mg
Capsule Oral 5 mg
Tablet, extended release Oral 10 mg
Tablet, extended release Oral 5 mg
Prices
Unit description Cost Unit
DynaCirc CR 10 mg 24 Hour tablet 5.59 USD tablet
Dynacirc cr 10 mg tablet 4.41 USD tablet
DynaCirc CR 5 mg 24 Hour tablet 3.0 USD tablet
Dynacirc cr 5 mg tablet 2.88 USD tablet
DynaCirc 5 mg capsule 2.31 USD capsule
Isradipine 5 mg capsule 2.0 USD capsule
DynaCirc 2.5 mg capsule 1.59 USD capsule
Isradipine 2.5 mg capsule 1.39 USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 168-170 °C Not Available
water solubility Practically insoluble (< 10 mg/L at 37 °C) Not Available
logP 4.28 SANGSTER (1994)
Predicted Properties
Property Value Source
water solubility 2.28e-01 g/l ALOGPS
logP 3 ALOGPS
logP 2 ChemAxon
logS -3.2 ALOGPS
pKa (strongest basic) 5.33 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 103.55 ChemAxon
rotatable bond count 6 ChemAxon
refractivity 100.08 ChemAxon
polarizability 37.39 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Fletcher H, Roberts G, Mullings A, Forrester T: An open trial comparing isradipine with hydralazine and methyl dopa in the treatment of patients with severe pre-eclampsia. J Obstet Gynaecol. 1999 May;19(3):235-8. Pubmed
  2. Ganz M, Mokabberi R, Sica DA: Comparison of blood pressure control with amlodipine and controlled-release isradipine: an open-label, drug substitution study. J Clin Hypertens (Greenwich). 2005 Apr;7(4 Suppl 1):27-31. Pubmed
  3. Hattori T, Wang PL: Calcium antagonist isradipine-induced calcium influx through nonselective cation channels in human gingival fibroblasts. Eur J Med Res. 2006 Mar 27;11(3):93-6. Pubmed
  4. Johnson BA, Roache JD, Ait-Daoud N, Wallace C, Wells L, Dawes M, Wang Y: Effects of isradipine, a dihydropyridine-class calcium-channel antagonist, on d-methamphetamine’s subjective and reinforcing effects. Int J Neuropsychopharmacol. 2005 Jun;8(2):203-13. Pubmed
External Links
Resource Link
KEGG Drug D00349 Link_out
PubChem Compound 3784 Link_out
PubChem Substance 46505034 Link_out
ChemSpider 3652 Link_out
Therapeutic Targets Database DAP000134 Link_out
PharmGKB PA450131 Link_out
RxList http://www.rxlist.com/cgi/generic2/israd.htm Link_out
Drugs.com http://www.drugs.com/cdi/isradipine.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/dyn1152.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Isradipine Link_out
ATC Codes
  • C08CA03
AHFS Codes
  • 24:28.08
PDB Entries Not Available
FDA label Not Available
MSDS show (57.4 KB)
Interactions
Drug Interactions
Drug Interaction
Artemether Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Lumefantrine Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Quinupristin This combination presents an increased risk of toxicity
Tacrolimus Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Telithromycin Telithromycin may reduce clearance of Isradipine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Isradipine if Telithromycin is initiated, discontinued or dose changed.
Thiopental The CYP3A4 inducer, Thiopental, may increase the metabolism and clearance of Isradipine, a CYP3A4 substrate. Monitor for changes in the therapeutic/adverse effects of Isradipine if Thiopental is initiated, discontinued or dose changed.
Thiothixene May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
Tipranavir Tipranavir may decrease the metabolism and clearance of the calcium channel blocker, Isradipine. Monitor for changes in Isradipine therapeutic and adverse effects if Tipranavir is initiated, discontinued or dose changed.
Toremifene Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Trimipramine Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of isradipine by decreasing its metabolism. Additive QTc prolongation may also occur. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of isradipine if voriconazole is initiated, discontinued or dose changed.
Vorinostat Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Ziprasidone Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
Zuclopenthixol Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Food Interactions Not Available
Targets

1. Voltage-dependent L-type calcium channel subunit alpha-1C

Pharmacological action: yes
Actions: inhibitor

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the "high-voltage activated" (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to DHP compounds

Organism class: human
UniProt ID: Q13936 Link_out
Gene: CACNA1C Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Berjukow S, Marksteiner R, Gapp F, Sinnegger MJ, Hering S: Molecular mechanism of calcium channel block by isradipine. Role of a drug-induced inactivated channel conformation. J Biol Chem. 2000 Jul 21;275(29):22114-20. Pubmed
  2. Hitzl M, Striessnig J, Neuhuber B, Flucher BE: A mutation in the beta interaction domain of the Ca(2+) channel alpha(1C) subunit reduces the affinity of the (+)-[(3)H]isradipine binding site. FEBS Lett. 2002 Jul 31;524(1-3):188-92. Pubmed
  3. Zuhlke RD, Bouron A, Soldatov NM, Reuter H: Ca2+ channel sensitivity towards the blocker isradipine is affected by alternative splicing of the human alpha1C subunit gene. FEBS Lett. 1998 May 8;427(2):220-4. Pubmed

2. Voltage-dependent calcium channel subunit alpha-2/delta-1

Pharmacological action: yes
Actions: inhibitor

Calcium channel protein which plays an important role in excitation-contraction coupling

Organism class: human
UniProt ID: P54289 Link_out
Gene: CACNA2D1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  2. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Voltage-dependent L-type calcium channel subunit beta-2

Pharmacological action: yes
Actions: inhibitor

The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting

Organism class: human
UniProt ID: Q08289 Link_out
Gene: CACNB2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Striessnig, J. (2004). Ca 2+ channel blockers. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology (pp. 201-207). Berlin, Germany: Springer.

4. Voltage-dependent T-type calcium channel subunit alpha-1H

Pharmacological action: yes
Actions: inhibitor

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1H gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by nickel and mibefradil. A particularity of this type of channels is an opening at quite negative potentials, and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes

Organism class: human
UniProt ID: O95180 Link_out
Gene: CACNA1H Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed
  2. Perez-Reyes E, Van Deusen AL, Vitko I: Molecular pharmacology of human Cav3.2 T-type Ca2+ channels: block by antihypertensives, antiarrhythmics, and their analogs. J Pharmacol Exp Ther. 2009 Feb;328(2):621-7. Epub 2008 Oct 30. Pubmed

5. Voltage-dependent calcium channel subunit alpha-2/delta-2

Pharmacological action: yes
Actions: inhibitor
Organism class: human
UniProt ID: Q9NY47 Link_out
Gene: CACNA2D2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed
  2. Perez-Reyes E, Van Deusen AL, Vitko I: Molecular pharmacology of human Cav3.2 T-type Ca2+ channels: block by antihypertensives, antiarrhythmics, and their analogs. J Pharmacol Exp Ther. 2009 Feb;328(2):621-7. Epub 2008 Oct 30. Pubmed

6. Voltage-dependent L-type calcium channel subunit alpha-1D

Pharmacological action: yes
Actions: inhibitor

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1D gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the "high-voltage activated" (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA)

Organism class: human
UniProt ID: Q01668 Link_out
Gene: CACNA1D Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Koschak A, Reimer D, Huber I, Grabner M, Glossmann H, Engel J, Striessnig J: alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages. J Biol Chem. 2001 Jun 22;276(25):22100-6. Epub 2001 Apr 2. Pubmed
  2. Sinnegger-Brauns MJ, Huber IG, Koschak A, Wild C, Obermair GJ, Einzinger U, Hoda JC, Sartori SB, Striessnig J: Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. Mol Pharmacol. 2009 Feb;75(2):407-14. Epub 2008 Nov 24. Pubmed

7. Voltage-dependent L-type calcium channel subunit alpha-1S

Pharmacological action: yes
Actions: inhibitor

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1S gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the "high-voltage activated" (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle

Organism class: human
UniProt ID: Q13698 Link_out
Gene: CACNA1S Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Peterson BZ, Catterall WA: Allosteric interactions required for high-affinity binding of dihydropyridine antagonists to Ca(V)1.1 Channels are modulated by calcium in the pore. Mol Pharmacol. 2006 Aug;70(2):667-75. Epub 2006 May 4. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19