Isradipine

Isradipine is an antihypertensive agent belonging to Calcium Channel Blocker.

Isradipine is used in the management of high blood pressure It works by relaxing the blood vessels which results in coronary vasodilation and reduction of blood pressure.

Almost completely absorbed from the gastrointestinal tract. Bioavailability is about 15-24%. Time to peak plasma concentration is approximately 1-1.5 hours. Isradipine crosses the placenta. Volume of distribution is about 3 L/kg. Plasma protein binding of Isradipine is approximately 95%. Extensively metabolized in the liver by CYP3A4 isoenzyme via oxidation and ester cleavage into 6 inactive metabolites; undergoes extensive first-pass hepatic metabolism. Completely metabolized prior to excretion and no unchanged drug is detected in the urine.

Isradipine shows common side effects like Bloating or swelling of face, arms, hands, lower legs, or feet, tingling of hands or feet, unusual weight gain or loss.

Isradipine is available in the form Oral tablet and Oral capsule.

Isradipine is available in India, US, UK, Europe, Ireland, China and Singapore.

Isradipine belonging to the Calcium Channel Blocker, acts as an antihypertensive agent.

Isradipine inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing relaxation of vascular smooth muscle, resulting in coronary vasodilation and reduced blood pressure; increases myocardial oxygen delivery in patients with vasospastic angina.

The onset of action of Isradipine occurs within 1 hour (by Conventional), 2 hours (by Sustain release).

The Duration of Action for Isradipine in the body is approximately 12 hours (by Conventional), 24 hours (by Sustain release).

The Tmax was found within 1.5-3 hours (by Conventional), and 7-18 hours (by Sustain release), following the administration of Isradipine.

Isradipine is available in the form of Oral tablet and capsule.

Isradipine Oral tablet and capsule taken by mouth usually once a day or twice a day.

Isradipine is a dihydropyridine calcium channel blocker used for the treatment of hypertension. It works by relaxing the blood vessels, so your heart does not have to pump as hard.

Isradipine is an antihypertensive agent belonging to calcium channel blocker.

Isradipine inhibits the transmembrane influx of extracellular Ca ions across the membranes of myocardial cells and vascular smooth muscle cells, without changing serum calcium concentrations, resulting in inhibition of cardiac and vascular smooth muscle contraction, thereby dilating the main coronary and systemic arteries.

Isradipine is approved for use in the following clinical indications

• Hypertension

Isradipine is indicated in the management of hypertension. It may be used alone or concurrently with thiazide-type diuretics.

• Hypertension

Adult Dose

Initial dose:

Immediate-release capsules: 2.5 mg orally twice a day

Controlled-release tablets: 5 mg orally once a day

Maintenance dose: The dose may be adjusted as needed and tolerated in increments of 5 mg at 2 to 4-week intervals.

Isradipine is available in various strengths as 2.5mg, 5mg, 10mg.

Isradipine is available in the form of Oral Tablet and capsule.

• Avoid drinking grapefruit juice or eating grapefruit while taking Isradipine.
• Avoid salt substitutes containing potassium and high-salt or high-sodium diet.

Isradipine is contraindicated in patients with

• Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of dihydropyridine calcium channel blockers. Reflex tachycardia may occur resulting in angina and/or MI in patients with obstructive coronary disease, especially in the absence of concurrent beta-blockade.
• Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; blood pressure must be lowered at a rate appropriate for the patient's clinical condition.
• Peripheral edema: A common side effect is peripheral edema (dose-dependent); may begin within 2 to 3 weeks of starting therapy.
• Aortic stenosis: Use with extreme caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.
• Heart failure (HF): The AHA/ACC/HFSA heart failure guidelines recommend avoiding use in patients with heart failure due to lack of benefit and/or worse outcomes with calcium channel blockers in general.
• Hepatic impairment: Use with caution in patients with hepatic impairment; may require lower starting dose.
• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Use with caution in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition.

Information is not available.

It is not known whether Isradipine is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects of Isradipine on nursing infants, a decision should be made as to whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pregnancy Category C

There are no adequate and well controlled studies in pregnant women. The use of Isradipine during pregnancy should only be considered if the potential benefit outweighs potential risks.

• Avoid drinking grapefruit juice or eating grapefruit while taking Isradipine.
• Avoid salt substitutes containing potassium and high-salt or high-sodium diet.

• Common Adverse effects

Edema flushing palpitations chest pain, tachycardia, Fatigue, dizziness, Skin rash, Nausea, abdominal distress, diaarhea, Weakness, urinary frequency, Dyspnea.

• Rare Adverse effects

Atrial fibrillation, cardiac failure, cerebrovascular accident, constipation, cough, decreased libido, depression, drowsiness, foot cramps, hyperhidrosis, hypotension, impotence, increased liver enzymes, insomnia, leg cramps, lethargy, leukopenia, myocardial infarction, nervousness, nocturia, numbness, paresthesia, pruritus, psoriasis (Song 2021), sore throat, syncope, transient ischemic attacks, urticaria, ventricular fibrillation, visual disturbance, xerostomia.

• Nitroglycerin

Isradipine has been safely coadministered with nitroglycerin.

• Hydrochlorothiazide

A study in normal healthy volunteers has shown that concomitant administration of Isradipine and hydrochlorothiazide does not result in altered pharmacokinetics of either drug. In a study in hypertensive patients, addition of Isradipine to existing hydrochlorothiazide therapy did not result in any unexpected adverse effects, and Isradipine had an additional antihypertensive effect.

• Propranolol

In a single dose study in normal volunteers, co-administration of propranolol had a small effect on the rate but no effect on the extent of Isradipine bioavailability. Significant increases in AUC (27%) and Cmax (58%) and decreases in tmax (23%) of propranolol were noted in this study. However, concomitant administration of 5 mg two times a day Isradipine and 40 mg two times a day propranolol to healthy volunteers under steady-state conditions had no relevant effect on either drug's bioavailability. AUC and Cmax differences were < 20% between Isradipine given singly and in combination with propranolol, and between propranolol given singly and in combination with Isradipine.

• Cimetidine

In a study in healthy volunteers, a one-week course of cimetidine at 400 mg two times a day with a single 5 mg dose of Isradipine on the sixth day showed an increase in Isradipine mean peak plasma concentrations (36%) and significant increase in area under the curve (50%). If Isradipine therapy is initiated in a patient currently receiving cimetidine, careful monitoring for adverse reactions is advised and downward dose adjustment may be required.

• Rifampicin

In a study in healthy volunteers, a six-day course of rifampicin at 600 mg/day followed by a single 5 mg dose of Isradipine resulted in a reduction in Isradipine levels to below detectable limits. If rifampicin therapy is required, Isradipine concentrations and therapeutic effects are likely to be markedly reduced or abolished as a consequence of increased metabolism and higher clearance of Isradipine.

• Warfarin

In a study in healthy volunteers, not clinically relevant pharmacokinetic or pharmacodynamic interaction between Isradipine and racemic warfarin was seen when two single oral doses of warfarin (0.7 mg/kg body weight) were administered during 11 days of multiple-dose treatment with 5 mg two times a day Isradipine. Neither racemic warfarin nor Isradipine binding to plasma proteins in vitro was altered by the addition of the other drug.

• Digoxin

The concomitant administration of Isradipine and digoxin in a single–dose pharmacokinetic study did not affect renal, nonrenal and total body clearance of digoxin.

• Fentanyl Anesthesia

Severe hypotension has been reported during fentanyl anesthesia with concomitant use of a beta blocker and a calcium channel blocker. Even though such interactions have not been seen in clinical studies with Isradipine, an increased volume of circulating fluids might be required if such an interaction were to occur.

The common side effects of Isradipine include the following

• Common
  

Bloating or swelling of face, arms, hands, lower legs, or feet, tingling of hands or feet, unusual weight gain or loss.

• Rare

Chest pain, difficult or labored breathing, dizziness, fast, irregular, pounding, or racing heartbeat or pulse, feeling of warmth, full or bloated feeling, nausea, pressure in the stomach, redness of the face, neck, arms and occasionally, upper chest, Dyspnea, swelling of abdominal or stomach area, tightness in chest, unusual tiredness or weakness, vomiting, wheezing.

• Pregnancy

Pregnancy Category C

Isradipine was administered orally to rats and rabbits during organogenesis. Treatment of pregnant rats with doses of 6, 20, or 60 mg/kg/day produced a significant reduction in maternal weight gain during treatment with the highest dose (150 times the maximum recommended human daily dose) but with no lasting effects on the mother or the offspring. Treatment of pregnant rabbits with doses of 1,3, or 10 mg/kg/day (2.5, 7.5, and 25 times the maximum recommended human daily dose) produced decrements in maternal body weight gain and increased fetal resorption at the two higher doses. There was no evidence of embryotoxicity at doses which were not maternotoxic and no evidence of teratogenicity at any dose tested. In a peri/postnatal administration study in rats, reduced maternal body weight gain during late pregnancy at oral doses of 20 and 60 mg/kg/day Isradipine was associated with reduced birth weights and decreased peri and postnatal pup survival.

There are no adequate and well controlled studies in pregnant women. The use of Isradipine during pregnancy should only be considered if the potential benefit outweighs potential risks.

• Nursing Mothers

It is not known whether Isradipine is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects of Isradipine on nursing infants, a decision should be made as to whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Symptoms: Lethargy, sinus tachycardia, excessive peripheral vasodilation; prolonged systemic hypotension and tachycardia.

Management: Symptomatic and supportive treatment. Induce emesis, perform gastric lavage, and administer activated charcoal followed in 30 minutes by saline cathartic. May administer vasoconstrictor (e.g., epinephrine, norepinephrine, levarterenol) for clinically significant hypotension. May administer IV Ca salts or glucagon for refractory hypotension or in atrioventricular conduction disturbances.

Pharmacodynamic

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.

Pharmacokinetics

• Absorption

Almost completely absorbed from the gastrointestinal tract. Bioavailability: 15-24%. Time to peak plasma concentration: 1-1.5 hours.

• Distribution

Crosses the placenta. Volume of distribution: 3 L/kg. Plasma protein binding: Approx 95%.

• Metabolism and Excretion

Extensively metabolized in the liver by CYP3A4 isoenzyme via oxidation and ester cleavage into 6 inactive metabolites; undergoes extensive first-pass metabolism. Hepatic. Completely metabolized prior to excretion and no unchanged drug is detected in the urine.

• https://www.uptodate.com/contents/isradipine-drug-information#F185299
• https://www.rxlist.com/dynacirc-drug.htm#interactions
• https://reference.medscape.com/drug/isradipine-342376#10
• https://www.drugs.com/mtm/isradipine.html
• https://www.mims.com/india/drug/info/isradipine?type=full&mtype=generic
• https://go.drugbank.com/drugs/DB00270
• https://medlineplus.gov/druginfo/meds/a693048.html#precautions