Chemical formula: C₁₉H₂₁N₃O₅ Molecular mass: 371.387 g/mol PubChem compound: 3784
Isradipine is a potent dihydropyridine calcium channel blocker with selective activity on voltage-gated calcium channels (L-type or “long acting”). Isradipine has a higher affinity for such calcium channels in arterial smooth muscle than for those in the myocardium. It thus dilates arterial vascular beds, in particular those of the heart, brain and skeletal muscle without depressing cardiac function. As a result of peripheral vasodilation, arterial blood pressure is lowered.
Experiments in animals and in man indicate that isradipine exerts a minimal depressant activity on the sinoatrial node automaticity, but does not impair atrioventricular conduction or myocardial contractile function. Reflex tachycardia is therefore moderate and no prolongation of the P-Q interval occurs, even after pretreatment with a β-blocker. Isradipine, at blood pressure lowering doses, has also been shown to possess moderate but significant natriuretic activity in animals and man and to exert an antiatherogenic effect in animals.
Treatment with isradipine slightly increases renal plasma flow and glomerular filtration rate, slightly decreases renal vascular resistance during the first 3 to 6 months of therapy. These changes were not maintained after 1 year of treatment but renal function was preserved in comparison to untreated hypertensive patients. Treatment with isradipine produces a sustained natriuretic and diuretic effect, which contributes to its antihypertensive effect. Calcium channel blockers have also exerted a renal protective effect in renal transplant patients receiving ciclosporin. Afferent arteriolar dilatation in particular seems to play a significant role there.
In hypertensive patients, a dose-related reduction in supine, sitting and standing blood pressure is achieved within 2 to 3 hours of administration of a single tablet. In therapeutic use, isradipine’s long duration of action ensures 24-hour control of arterial blood pressure with twice daily administration of tablets or once daily administration of an SRO capsule. Significant lowering of blood pressure is seen after one week of treatment, but at least 3 to 4 weeks are required for the maximum effect to develop.
With tablets, increases in the resting heart rate are minimal (less than 5 beats/minute) and not dosedependent.
Changes in heart rate have not usually been observed with SRO capsules.
Isradipine has been well tolerated when given at doses of up to 20 and 22.5 mg/day to patients with hypertension or stable angina pectoris.
Single oral doses of isradipine blunted the bronchospastic response of asthmatic patients to exercise.
Because it has no clinically relevant effect on glucose homoeostasis, isradipine may be given to diabetic patients.
No diminution of the antihypertensive effect of isradipine occurred in studies lasting up to 2 years.
After 90 to 95% absorption from the gastrointestinal tract, isradipine undergoes extensive first-pass metabolism resulting in a bioavailability of about 16 to 18%.
After doses of up to 20 mg, both the peak plasma concentration and the area under the curve exhibit a linear relationship with the dose.
About 50% of the isradipine contained in isradipine capsules is absorbed within 10 hours, and the peak plasma concentration is reached approximately 5 to 7 hours after administration. The peak plasma concentration (Cmax) is 1 ng/mL for a single dose 5 mg SRO capsules and 1.8 ng/mL at steady state.
Ingestion of the SRO capsule with food leads to slightly higher peak plasma concentrations and increases the bioavailability of isradipine by about 20%.
Isradipine is about 95% bound to plasma proteins and its apparent distribution volume is 283 L.
Isradipine is extensively biotransformed in the liver by deesterification and aromatisation of the dihydropyridine moiety. Five metabolites of isradipine account for 95% of the dose of the parent compound. In vitro data showed that none of these metabolites contribute to the cardiovascular effects of isradipine.
The total clearance of isradipine is 43 L/hour. Its elimination is biphasic, with a terminal half-life of 8.4 hours. About 60 to 65% of an administered dose is excreted in the urine and 25 to 30% in the faeces as metabolites. No unchanged drug has been detectable in the urine.
Data have shown no clear correlation between renal function and bioavailability, both an increase and a decrease in creatinine clearance and systemic clearance of isradipine has been observed in patients with impaired renal function.
Bioavailability has been reported to be higher in elderly patients and in patients with impaired liver function, reaching increases of up to 27%.
Preclinical data-based on conventional studies of single and multiple dose toxicity reveal no special hazard for humans. There is no genotoxic, clastogenic or carcinogenic potential. Animal studies do not show any harmful effects on fertility. Embryotoxic effects were noted only at maternally toxic doses. There was no evidence of teratogenicity of isradipine.
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