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QuickView for isradipine (compound)

Summary
General Info

PubChem

PubChem Compound 158617

PubChem Compound 158617

Name:	Isradipine
PubChem Compound ID:	158617
Description:	A potent antagonist of CALCIUM CHANNELS that is highly selective for VASCULAR SMOOTH MUSCLE. It is effective in the treatment of chronic stable angina pectoris, hypertension, and congestive cardiac failure.
Molecular formula:	C₁₉H₂₁N₃O₅
Molecular weight:	371.387 g/mol
Synonyms:	84260-64-0; NCGC00016931-01; NCGC00025341-01; Tocris-2004; CAS-75695-93-1; 3,5-Pyridinedicarboxylic acid, 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-, methyl 1-methylethyl ester, (4S)-

DrugBank

Identification

Name:	Isradipine
Name (isomeric):	DB00270
Drug Type:	small molecule
Description:	A potent antagonist of CALCIUM CHANNELS that is highly selective for VASCULAR SMOOTH MUSCLE. It is effective in the treatment of chronic stable angina pectoris, hypertension, and congestive cardiac failure.
Synonyms:	Isrodipine; Isradipino [Spanish]; Isradipinum [Latin]; (+/-)-Isradipine; Isradipin
Brand:	Clivoten, Prescal, Dynacrine, DynaCirc, Lomir, Rebriden, Esradin, DynaCire, Dynacirc CR, DynaCire CR
Category:	Vasodilator Agents, Calcium Channel Blockers, Antihypertensive Agents
CAS number:	75695-93-1

Pharmacology

Indication:	For the management of mild to moderate essential hypertension. It may be used alone or concurrently with thiazide-type diuretics.
Pharmacology:	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 ... show more » 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. show less «
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 ot... show more » 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. show less «
Absorption:	Isradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%.
Protein binding:	95%
Biotransformation:	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
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

Interactions

Drug interaction:

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.
Vorinostat	Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
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.
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.
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.

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.
Vorinostat	Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
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.
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.
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.
Ziprasidone	Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
Quinupristin	This combination presents an increased risk of toxicity
Artemether	Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Tacrolimus	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Lumefantrine	Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
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.
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).
Trimipramine	Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Treprostinil	Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
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.

Targets

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

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

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

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

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

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

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

Enzymes

Cytochrome P450 3A4