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Identification
NameIsradipine
Accession NumberDB00270  (APRD00298)
TypeSmall Molecule
GroupsApproved
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
Synonyms
SynonymLanguageCode
DynacircNot AvailableNot Available
IsradipinoSpanishNot Available
IsradipinumLatinNot Available
Prescription ProductsNot Available
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Isradipinecapsule2.5 mgoralActavis Pharma, Inc.2004-01-05Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Isradipinecapsule5 mgoralActavis Pharma, Inc.2006-01-05Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Isradipinecapsule2.5 mgoralEpic Pharma, LLC2014-05-15Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Isradipinecapsule5 mgoralEpic Pharma, LLC2014-05-15Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Isradipinecapsule2.5 mgoralAv Pak2014-01-06Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Isradipinecapsule5 mgoralAv Pak2014-01-06Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Isradipinecapsule5 mgoralCarilion Materials Management2006-01-05Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Over the Counter ProductsNot Available
International Brands
NameCompany
ClivotenItalfarmaco (Italy)
DynaCircNovartis (Hong Kong, Malaysia, Mexico, New Zealand, South Africa, Singapore, Thailand, Turkey, United States)
Dynacirc CRReliant, GlaxoSmithKline
EsradinSigma-Tau (Italy)
LomirNovartis (Austria, Brazil, Czech Republic, Denmark, Finland, Germany, Greece, Hungary, Netherlands, Norway, Poland, Russia, Sweden), Sankyo (Belgium, Italy), Daiichi Sankyo (Portugal, Switzerland), Mizar (Spain)
PrescalNovartis (United Kingdom)
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number75695-93-1
WeightAverage: 371.3871
Monoisotopic: 371.148120797
Chemical FormulaC19H21N3O5
InChI KeyHMJIYCCIJYRONP-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
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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as benzoxadiazoles. These are organic compounds containing a benzene fused to an oxadiazole ring (a five-membered ring with two carbon atoms, one nitrogen atom, and one oxygen atom).
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzoxadiazoles
Sub ClassNot Available
Direct ParentBenzoxadiazoles
Alternative Parents
Substituents
  • Dihydropyridinecarboxylic acid derivative
  • Benzoxadiazole
  • Dihydropyridine
  • Benzenoid
  • Hydropyridine
  • Dicarboxylic acid or derivatives
  • Heteroaromatic compound
  • Vinylogous amide
  • Alpha,beta-unsaturated carboxylic ester
  • Enoate ester
  • Methyl ester
  • Oxadiazole
  • Furazan
  • Azole
  • Carboxylic acid ester
  • Oxacycle
  • Azacycle
  • Enamine
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the management of mild to moderate essential hypertension. It may be used alone or concurrently with thiazide-type diuretics.
PharmacodynamicsIsradipine 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 actionIsradipine 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.
AbsorptionIsradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%.
Volume of distributionNot Available
Protein binding95%
Metabolism

Hepatic. Completely metabolized prior to excretion and no unchanged drug is detected in the urine.

Route of eliminationApproximately 60% to 65% of an administered dose is excreted in the urine and 25% to 30% in the feces.
Half life8 hours
ClearanceNot Available
ToxicitySymptoms 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
PathwayCategorySMPDB ID
Isradipine Action PathwayDrug actionSMP00378
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9965
Blood Brain Barrier-0.8439
Caco-2 permeable+0.8867
P-glycoprotein substrateSubstrate0.5855
P-glycoprotein inhibitor IInhibitor0.9322
P-glycoprotein inhibitor IIInhibitor0.8669
Renal organic cation transporterNon-inhibitor0.884
CYP450 2C9 substrateNon-substrate0.8522
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.6631
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 substrateInhibitor0.8949
CYP450 2D6 substrateNon-inhibitor0.9231
CYP450 2C19 substrateInhibitor0.8994
CYP450 3A4 substrateInhibitor0.796
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8557
Ames testNon AMES toxic0.5158
CarcinogenicityNon-carcinogens0.8043
BiodegradationNot ready biodegradable0.9747
Rat acute toxicity2.3960 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8699
hERG inhibition (predictor II)Non-inhibitor0.6895
Pharmacoeconomics
Manufacturers
  • Smithkline beecham corp dba glaxosmithkline
  • Actavis totowa llc
  • Watson laboratories inc
  • Glaxosmithkline llc
Packagers
Dosage forms
FormRouteStrength
Capsuleoral2.5 mg
Capsuleoral5 mg
Prices
Unit descriptionCostUnit
DynaCirc CR 10 mg 24 Hour tablet5.59USD tablet
Dynacirc cr 10 mg tablet4.41USD tablet
DynaCirc CR 5 mg 24 Hour tablet3.0USD tablet
Dynacirc cr 5 mg tablet2.88USD tablet
DynaCirc 5 mg capsule2.31USD capsule
Isradipine 5 mg capsule2.0USD capsule
DynaCirc 2.5 mg capsule1.59USD capsule
Isradipine 2.5 mg capsule1.39USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point168-170 °CNot Available
water solubilityPractically insoluble (< 10 mg/L at 37 °C)Not Available
logP4.28SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.228 mg/mLALOGPS
logP3ALOGPS
logP2ChemAxon
logS-3.2ALOGPS
pKa (Strongest Basic)5.33ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area103.55 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity100.08 m3·mol-1ChemAxon
Polarizability37.39 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot 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
ATC CodesC08CA03
AHFS Codes
  • 24:28.08
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (57.4 KB)
Interactions
Drug Interactions
Drug
ArtemetherAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
LumefantrineAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
QuinupristinThis combination presents an increased risk of toxicity
TacrolimusAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
TelithromycinTelithromycin 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.
ThiopentalThe 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.
ThiothixeneMay cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
TipranavirTipranavir 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.
ToremifeneAdditive 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.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
TrimipramineAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
VoriconazoleVoriconazole, 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.
VorinostatAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
ZiprasidoneAdditive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
ZuclopenthixolAdditive 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 InteractionsNot Available

Targets

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent L-type calcium channel subunit alpha-1C Q13936 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent calcium channel subunit alpha-2/delta-1 P54289 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent L-type calcium channel subunit beta-2 Q08289 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent T-type calcium channel subunit alpha-1H O95180 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent calcium channel subunit alpha-2/delta-2 Q9NY47 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent L-type calcium channel subunit alpha-1D Q01668 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent L-type calcium channel subunit alpha-1S Q13698 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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
  2. Lexicomp

Comments
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Drug created on June 13, 2005 07:24 / Updated on September 25, 2013 18:05