Isradipine

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Abstract
Isradipine, a dihydropyridine derivative, inhibits the inward calcium flux through ‘slow’ channels of cardiac and vascular tissue, thereby eliciting potent coronary, cerebral and peripheral vasodilatation. In comparison with other calcium channel blockers the drug offers the advantages of minimal cardiodepressant activity, a selective action on the coronary and skeletal muscle vasculature, and a prolonged vasodilatory action. Clinical trials indicate that isradipine is an effective antihypertensive agent, suitable as monotherapy or in combination with β-blockers, diuretics or ACE inhibitors, for long term treatment of mild to moderate hypertension. Preliminary findings suggest that the drug has a potential role in the treatment of chronic stable angina and, possibly, congestive heart failure. Adverse effects associated with the vasodilatory action of isradipine are generally mild, transient and well-tolerated, and are similar to those encountered with other calcium channel blockers. Thus, isradipine appears to offer a useful alternative to other dihydropyridine derivatives currently employed for the treatment of mild to moderate hypertension and, to a lesser extent, chronic stable angina. While its relative freedom from serious adverse effects may prove of value, its place in therapy vis-à-vis the established calcium channel blockers requires further clarification. Isradipine, in common with other calcium channel blockers, produces preferential blockade of voltage-operated calcium channels, thereby inhibiting the ‘slow’ channel influx of calcium into cardiac and vascular tissue. Its high degree of selectivity for coronary, cerebral and skeletal muscle vasculature confers potent vasodilatory activity, particularly on the arterial side of the circulation, and accounts for the drug’s pronounced antihypertensive action. In vitro animal studies indicate that isradipine has a selective depressant effect on sinoatrial node automaticity, a less pronounced inhibitory action on atrioventricular node conduction and no effect on intraventricular conduction, while its negative inotropic actions are manifest at substantially higher concentrations than its electro-physiological actions. In humans, isradipine has minimal depressant activity on sinoatrial node automaticity and negligible negative chronotropic, dromotropic and inotropic actions. In vitro investigations in animal tissues indicate that, of the calcium channel blockers, isradipine is inferior only to nifedipine and darodipine in its coronary vasodilator potency, while its selectivity for coronary over cardiac tissues is more marked than that of nicardipine, nisoldipine, nimodipine and darodipine. Similarly, isradipine shows marked selectivity for vascular smooth muscle over cardiac tissue. In vivo animal experiments indicate that the effects of isradipine on regional circulation are consistent with the general pattern observed with other dihydropyridine derivatives (viz. increased coronary, brain and skeletal muscle blood flow and reduced renal blood flow) but are typically longer lasting. Acute haemodynamic studies in humans suggest that isradipine induces selective arterial vasodilatation, reducing blood pressure and systemic vascular resistance without altering cardiac filling pressures, and produces secondary increases in cardiac output and stroke volume as the result of afterload reduction. Reflex tachycardia is either slight or absent, and the negative inotropic effects, which are counterbalanced by the reflex sympathetic activation associated with isradipine-induced vasodilatation, are less marked than with nifedipine. Short and long term isradipine administration is accompanied by sustained diuretic and natriuretic effects in hypertensive patients. Plasma renin activity is variously increased or unaltered by isradipine administration in these patients, and the antihypertensive efficacy of isradipine is not obviously related to pretreatment plasma renin activity. Isradipine shows antiatherogenic effects in the cholesterol-fed rabbit at doses in the therapeutic range of human use and, moreover, does not appear to have a detrimental effect on the serum lipid profile in man. The question of whether isradipine can retard the progression of atherosclerotic lesions in humans is currently under investigation. Isradipine is rapidly and virtually completely absorbed from the gastrointestinal tract. It undergoes extensive first-pass hepatic metabolism, resulting in a bioavailability of approximately 17% with oral doses of 5 to 20mg. The pharmacokinetics of isradipine are linear in this dose range, and peak plasma levels (≈ 2 to 10 μg/L with capsule formulations) are attained within 2.5 hours of oral administration. Isradipine is a lipophilic compound which is approximately 97% bound to plasma proteins (predominantly α1 -acid glycoprotein). Information regarding its tissue distribution is limited. The volume of distribution of the drug is ≈ 2.9 L/kg at steady-state. Isradipine undergoes extensive hepatic biotransformation to yield pharmacologically inactive metabolites which remain detectable in the urine for up to 96 hours following a single oral dose. The urine: faeces excretion ratio is 70: 30, with approximately 10% of the parent compound being excreted unchanged in the faeces. Isradipine shows a biphasic elimination pattern; the effective elimination half-life of isradipine is 8.8 hours, and appears unrelated to dose. The bioavailability of isradipine is enhanced in elderly subjects and in patients with impaired hepatic (but apparently not renal) function, indicating that dosage modification may be appropriate in these subgroups. Open and placebo-controlled trials of up to 2 years duration have suggested that isradipine (typically in doses of 2.5 to 10mg...