Isradipine

Pronunciation

(iz RA di peen)

U.S. Brand Names

DynaCirc®; DynaCirc® CR

Generic Available

Canadian Brand Names

DynaCirc®

Use

Treatment of hypertension

Pregnancy Risk Factor

Pregnancy Implications

No data on crossing the placenta

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to isradipine or any component of the formulation; hypotension (<90 mm Hg systolic)

Warnings/Precautions

Use cautiously in CHF, hypertrophic cardiomyopathy (IHSS), and in hepatic dysfunction. Safety and efficacy have not been established in pediatric patients. Adjust doses at 2- to 4-week intervals.

Adverse Reactions

>10%: Central nervous system: Headache (dose related 2% to 22%)

1% to 10%:

Cardiovascular: Edema (dose related 1% to 9%), palpitation (dose related 1% to 5%), flushing (dose related 1% to 5%), tachycardia (1% to 3%), chest pain (2% to 3%)

Central nervous system: Dizziness (2% to 8%), fatigue (dose related 1% to 9%), flushing (9%)

Dermatologic: Rash (1.5% to 2%)

Gastrointestinal: Nausea (1% to 5%), abdominal discomfort ( 3%), vomiting ( 1%), diarrhea ( 3%)

Renal: Urinary frequency (1% to 3%)

Respiratory: Dyspnea (1% to 3%)

0.5% to 1% (Limited to important or life-threatening): Pruritus, urticaria, cramps of legs and feet, cough, dyspnea, hypotension, atrial fibrillation, ventricular fibrillation, MI, heart failure, abdominal discomfort, constipation, diarrhea, nocturia, drowsiness, insomnia, lethargy, nervousness, weakness, impotence, decreased libido, depression, syncope, paresthesia,transient ischemic attack, stroke, hyperhidrosis, visual disturbance, dry mouth, gingival hyperplasia (incidence unknown), numbness, throat discomfort, leukopenia, elevated liver function tests

Overdosage/Toxicology

Primary cardiac symptoms of calcium blocker overdose include hypotension and bradycardia. Hypotension is caused by peripheral vasodilation, myocardial depression, and bradycardia. Bradycardia results from sinus bradycardia, second- or third-degree atrioventricular block, or sinus arrest with junctional rhythm. Intraventricular conduction is usually not affected so QRS duration is normal (verapamil does prolong the PR interval and bepridil prolongs the QT interval and may cause ventricular arrhythmias, including torsade de pointes).

Noncardiac symptoms include confusion, stupor, nausea, vomiting, metabolic acidosis and hyperglycemia. Repeated calcium administration may promptly reverse the depressed cardiac contractility (but not sinus node depression or peripheral vasodilation).

Drug Interactions

Substrate of CYP3A4 (major); Inhibits CYP3A4 (weak)

Azole antifungals may inhibit the calcium channel blocker's metabolism; avoid this combination. Try an antifungal like terbinafine (if appropriate) or monitor closely for altered effect of the calcium channel blocker.

Beta-blockers may have increased pharmacokinetic or pharmacodynamic interactions with isradipine.

Calcium may reduce the effect of calcium channel blockers, particularly hypotension.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of isradipine. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of isradipine. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Rifampin increases the metabolism of the calcium channel blocker; adjust the dose of the calcium channel blocker to maintain efficacy.

Sildenafil, tadalafil, vardenafil: Blood pressure-lowering effects may be additive; use caution.

Ethanol/Nutrition/Herb Interactions

Food: Administration with food delays absorption, but does not affect availability

Herb/Nutraceutical: St John's wort may decrease isradipine levels. Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effect).

Mechanism of Action

Inhibits calcium ion from entering the "slow channels" or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina

Pharmacodynamics/Kinetics

Duration: 8-16 hours

Absorption: 90% to 95%

Protein binding: 95%

Metabolism: Hepatic; extensive first-pass effect

Bioavailability: 15% to 24%

Half-life elimination: 8 hours

Time to peak, serum: 1-1.5 hours

Excretion: Urine (as metabolites)

Dosage

Oral: Adults: 2.5 mg twice daily; antihypertensive response occurs in 2-3 hours; maximal response in 2-4 weeks; increase dose at 2- to 4-week intervals at 2.5-5 mg increments; usual dose range (JNC 7): 2.5-10 mg/day in 2 divided doses. Note: Most patients show no improvement with doses >10 mg/day except adverse reaction rate increases; therefore, maximal dose in older adults should be 10 mg/day.

Administration

May open capsule; avoid crushing contents

Dietary Considerations

May be taken without regard to meals.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take as prescribed, with or without food. Do not stop abruptly without consulting prescriber. Do not crush extended release tablets. This medication does not replace other antihypertensive interventions; follow prescriber's instructions for diet and lifestyle changes. You may experience headache (if unrelieved, consult prescriber for approved analgesic); nausea or vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased dietary bulk and fluids may help); or dizziness, fatigue, confusion (use caution when driving or engaging in potentially hazardous tasks until response to drug is known). Report unrelieved headache, vomiting, or constipation; chest pain, palpitations, or rapid heartbeat; swelling of hands or feet or sudden weight gain (>5 lb/week); or unusual cramps in legs or feet. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Cardiovascular Considerations

Isradipine alone or in combination with other agents is effective in the management of hypertension.

In the treatment of unstable angina/non-ST-segment elevation MI, a nondihydropyridine calcium antagonist (diltiazem or verapamil) may be considered in patients with continuing or frequently recurring ischemia when beta-blockers are contraindicated (Class I). Oral long-acting calcium antagonists may also be considered in addition to beta-blockers and nitrates (Class IIa).

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause dizziness or drowsiness

Mental Health: Effects on Psychiatric Treatment

None reported

Dosage Forms

Capsule (DynaCirc®): 2.5 mg, 5 mg

Tablet, controlled release (DynaCirc® CR): 5 mg, 10 mg

Extemporaneously Prepared

A 1 mg/mL oral liquid was stable for 35 days when refrigerated when compounded as follows:

Dissolve the contents of ten 5 mg capsules in simple syrup, qs ad 50 mL

Shake well before using and keep in refrigerator

MacDonald JL, Johnson CE, and Jacobson P, "Stability of Isradipine in Extemporaneously Compounded Oral Liquids," Am J Hosp Pharm , 1994, 51(19):2409-11.

References

Braunwald E, Antman EM, Beasley JW, et al, "ACC/AHA Guidelines for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina)," J Am Coll Cardiol , 2000, 36(3):970-1062.

Chobanian AV, Bakris GL, Black HR, et al, "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report," JAMA , 2003, 289(19):2560-71.

Steele RM, Schuna AA, and Schreiber RT, "Calcium Antagonist-Induced Gingival Hyperplasia," Ann Intern Med , 1994, 120(8):663-4.

International Brand Names

Clivoten® (IT); Dilatol® (PT); DynaCirc® (AR, CA, CL, CO, CR, DO, HK, HN, MX, NZ, PA, SG, SV, TH, TR, ZA); Esradin® (IT); Icaz® (FR); Lomir® (AT, BD, BE, BR, CH, CZ, DE, DK, ES, FI, HU, IT, LU, MT, NL, NO, PT, RO, RU, SE); Lomir SRO® (AT, CH, CZ, DE, PL, SE); Prescal® (GB); Tenzipin® (SI); Vascal® (DE)

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