- 25 Downloads
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 twice daily) normalises systolic and diastolic blood pressure in up to 85% of patients with mild to moderate hypertension. The drug’s antihypertensive efficacy appears to be unrelated to patients’ age or race. Results from comparative studies indicate that the medium term antihypertensive efficacy pf isradipine is comparable to that of nifedipine and hydrochlorothiazide, and possibly superior to that of propranolol atenolol, prazosin and diltiazem. In combination with the β-blocker pindolol or the ACE inhibitor captopril, isradipine is effective in restoring blood pressure to normotensive levels in patients inadequately controlled by monotherapy.
Comparative trials of 4 to 6 weeks duration, albeit limited in number, have indicated that isradipine (2.5 to 7.5mg 3 times daily) is of similar efficacy to nifedipine and isosorbide dinitrate in improving exercise performance and reducing the frequency of anginal attacks in patients with chronic stable angina.
The majority of reported adverse effects of isradipine — headache, flushing, ankle oedema, dizziness and palpitations/tachycardia — are related to the drug’s vasodilatory action and are commonly encountered with other calcium channel blockers. These side effects are generally mild, dose-related and transient, occurring most frequently during the initial weeks of therapy and subsiding with continued treatment. The incidence of adverse effects with low dose isradipine therapy (≤ 5mg twice daily) is comparable to that seen with placebo, ranging from 15 to 30% of patients; facial erythema and hot flushes in particular are more frequent with higher doses (> 15 mg/day). The overall tolerability of isradipine has been assessed as good or very good in 86% of patients, and compares favourably with that of nifedipine.
Steady-state digoxin concentrations are not significantly altered by isradipine pretreatment and no special precautions appear to be necessary when the 2 drugs are jointly administered. Peak plasma propranolol concentrations are elevated by concomitant isradipine administration, although the clinical significance of this observation is unclear.
Dosage and Administration
In patients with mild to moderate hypertension, the optimum response, both with isradipine monotherapy and with β-blocker combination therapy, occurs with doses ranging from 2.5 to 7.5mg twice daily. Doses should be titrated to individual patient responses, commencing with an initial dose of 2.5mg twice daily, and dose increments should be performed at intervals of at least 4 weeks to avoid unnecessarily high doses. For patients with chronic stable angina, a regimen of isradipine 2.5 to 7.5mg 3 times daily appears appropriate.
KeywordsNifedipine Diltiazem Calcium Antagonist Nicardipine Nitrendipine
Unable to display preview. Download preview PDF.
- Arge K. An overview of safety and efficacy of nicardipine in clinical trials. American Journal of Cardiology 59 (Suppl. J): 31–35, 1987Google Scholar
- Björck S, Nyberg G, Mulec H, Granerus G, Herlitz H, et al. Beneficial effects of angiotensin converting enzyme inhibition on renal function in patients with diabetic nephropathy. British Medical Joufnal 293: 471–474, 1986Google Scholar
- Boutagy J, Rumble F, Gilmour M, Stokes G, Shenfield G. High performance liquid chromatography (HPLC) of isradipine (PN 200-110) - application to a clinical trial. Abstract no. 172. Clinical and Experimental Pharmacology and Physiology (Suppl. 11), 1987Google Scholar
- Brister NW, Barnette RE, Schartel SA, Cavarocchi NC. Isradipine for blood pressure reduction following myocardial revascularization. Abstract. Anesthesiology 71 (Suppl. 3A): A195, 1989Google Scholar
- British Isradipine Hypertension Group. Evaluation of the safety and efficacy of isradipine in elderly patients with essential hypertension. American Journal of Medicine 86 (Suppl. 4A): 110–114, 1989Google Scholar
- Bühler F, Kiowski W. Age and antihypertensive response to calcium antagonists. Journal of Hypertension 5 (Suppl. 4): 111–114, 1987Google Scholar
- Carruthers SG. Dynamic interaction between atenolol and the calcium blocker PN 200-110. Abstract no. 508. Acta Pharmacologica et Toxicologica 59 (Suppl. 5): 180, 1986Google Scholar
- Cauvin C, Hwang O, Yamamoto M, van Breemen C. Effects of dihydropyridines on tension and calcium-45 influx in isolated mesenteric resistance vessels from spontaneously hypertensive and normotensive rats. American Journal of Cardiology 59: 116B-122B, 1987Google Scholar
- Cavero I, Boudot J-P, Feuvray D. Diltiazem protects the isolated rabbit heart from the mechanical and ultrastruptural damage produced by transient hypoxia, low flow ischemia and exposure to Ca2+ -free medium. Journal of Pharmacology and Experimental Therapeutics 226: 258–268, 1983PubMedGoogle Scholar
- Chellingsworth MC, Willis JV, Jack DB, Kendall MJ. Pharmacokinetics and pharmacodynamics of isradipine (PN 200-110) in young and elderly patients. American Journal of Medicine 84 (Suppl, 3B): 72–79, 1988Google Scholar
- Davis D, Baily RG, Deiling SM, Zelis R. Failure of tolerance to develop to the acute renal and splanchnic vasodilator effects of the calcium-blocker PN 200-110 in patients with congestive heart failure. Abstract no. 1019. Circulation 76 (Suppl. IV): 256, 1987Google Scholar
- DeLeeuw PW, BirKenhäger WH. Effects of verapamil in hypertensive patients. Acta Medica Scandinavica (Suppl. 681): 125‐128, 1984Google Scholar
- Devis G, Somers G, Van Obberghen E, Malaisse WJ. Calcium antagonists and islet function.I. Inhibition by verapamil. Diabetes 2.4: 547–551, 1975Google Scholar
- Drake-Holland AJ. Biochemical features of myocardial ischemia. In Protection of Tissues against Hypoxia, Wauquier A, Borgers M, Amery WK (Eds), pp. 87–93, Elsevier, Amsterdam, 1982Google Scholar
- Edgar B. Clinical pharmacokinetics of felodipine. Ph.D Thesis, University of Göteborg, 1988Google Scholar
- Fisher CA, Josephson ME, Wacht-Fogel YT, Colman RW, Addonizio VP. Verapamil and diltiazem as antiplatelet agents: Spectrum and mechanisms of activity. Circulation 68 (Suppl. III): 318, 1983Google Scholar
- Frey M, Keidel J, Fleckenstein A. Verhütung experimenteller Gefässverkalkungen (Mönckebergs Typ der Arteriosklerose) durch Calcium-Antagonisten bei Ratten. In Fleckenstein A and Roskamm H (Eds) Calcium-Antagonismus, pp. 258–285, Springer, Berlin, 1980Google Scholar
- Ginsberg R, David K, Bristow MR, McKennel K, Kodel SR, et al. Calcium antagonists suppress atherogenesis in aorta but not in intramural coronary arteries of cholesterol-fed rabbits. Laboratory Investigation 49: 154–158, 1983Google Scholar
- Greenberg B, Siemienczuk D, Broudy D. Hemodynamic effects of PN 200-110 (isradipine) in congestive heart failure. American Journal of Cardiology 59: 70B-74B, 1987Google Scholar
- Hamilton J, Kuzbida G, Pavlis R, Hamilton B. Isradipine, a new calcium channel blocker for mild to moderate hypertension in older blacks. Abstract. Journal of Human Hypertension 2: 281, 1988Google Scholar
- Hamm CW, Opie LH. Protection of infarcting myocardium by slow channel inhibitors. Circulation Research 50: 1129–1138, 1983Google Scholar
- Henry PD, Bentley KL Suppression of atherogenesis in cholesterol-fed rabbits treated with nifedipine. Journal of Clinical In-vestigation 68: 1366–1369, 1981Google Scholar
- Henry PD, Shuchleib R, Davis J, Weiss ES, Sobel BE. Myocardial contracture and accumulation of mitochondrial calcium in is-chemic rabbit heart. American Journal of Physiology 223: H677–H684, 1977Google Scholar
- Hof R. Pharmacology of a new calcium antagonist, isradipine with target tissue selectivity. Second Cardiovascular Pharmacother-apy Symposium, October 18th 1987, San Francisco, Califor-nia, 1987bGoogle Scholar
- Hof R, Rüegg UT. Pharmacology of the new calcium antagonist isradipine and its metabolites. American Journal of Medicine 84(Suppl. 3B): 13–17, 1988Google Scholar
- Hof RP, Scholtysik G, Loutzenhiser R, Vuorela HJ, Neumann P. PN 200-110, a new calcium antagonist: electrophysiological, inotropic and chronotropic effects on guinea pig myocardial tissue and effects on contraction and calcium uptake of rabbit aorta. Journal of Cardiovascular Pharmacology 6: 399–406, 1984bPubMedGoogle Scholar
- Hulthén UL, Bolli P, Bühler FR. Calcium influx blockers in the treatment of essential hypertension. Acta Medica Scandinavica Suppl. 681: 101–108, 1984Google Scholar
- Isradipine in Hypertension Study Group. A multicenter evaluation of the safety and efficacy of isradipine and atenolol in the treatment of hypertension. American Journal of Medicine 86 (Suppl. 4A): 119–123, 1989Google Scholar
- Italian-Belgian Isradipine Study Group. Multicenter evaluation of the safety and efficacy of isradipine in hypertension. American Journal of Medicine 86 (Suppl. 4A): 94–97, 1989Google Scholar
- Jie K, van Brummelen P, Timmermans PB, Thoolen MJ, van Zwieten PA. Effects of PN 200-110, a new calcium antagonist, on α1 - and α2 -adrenoceptor mediated vasoconstriction elicited by selective a-adrenoceptor agonists and catecholamines in the pithed rat. Archives Internationales de Pharmacodynamie et de Therapie 278: 72–86, 1985PubMedGoogle Scholar
- Kazda S, Knorr A, Towart R. Common properties and differences between various calcium antagonists. Progress in Pharmacology 5: 83–116, 1983Google Scholar
- Kiowski W, Bühler FR, Fadayomi MO, Erne P, Müller FB, et al. Age, race, blood pressure and renin: predictors for antihypertensive treatment with calcium antagonists. American Journal of Cardiology 56: 81H-85H, 1985Google Scholar
- Kirkendall WM. Comparative assessment of first-line agents for treatment of hypertension. American Journal of Medicine 84 (Suppl. 3B): 32–41, 1988Google Scholar
- Landau S, Kaminetzky JS, Hogan C, Tepper D, Tullo N, et al. Comparison of the cardiac electrophysiologic effects of isradipine and verapamil in man. Abstract no. 5. Journal of Clinical Pharmacology 28: 909, 1988Google Scholar
- Margolis B, Lucas C, Henry PD. Effects of Ca++ -antagonists on platelet aggregation and secretion. Circulation 62 (Pt 2): 191, 1980Google Scholar
- Mitchell AD, Steiner TJ. Nimodipine — a calcium antagonist in stroke therapy? In Breenhalgh RM, Rose FC (Eds) Progress in Stroke Research 2. pp. 315–323, Pitman fress, Bath, UK, 1983Google Scholar
- Niederberger W, Gonasun LM, Kutz K. A population pharmacokinetic study during phase III clinical trials for the calcium antagonist PB 200-110. Third European Congress of Biopharmaceutics and Pharmacokinetics, Freiburg, Federal Republic of Germany, April 1986Google Scholar
- Pagani G, Lancranjan I, Marbach P, Gianola D, Pagani MD, et al. PN200-110, a new Ca++ antagonist, failed to affect GH secretion in acromegaly. Abstract 1–15. 1st European Congress of Endocrinology, June 21–25, 1987Google Scholar
- Parratt JR. In Parratt (Ed.) Control and manipulation of calcium movement: a biological council symposium. Raven Press, New York, 1985Google Scholar
- Pool PE, Seagren SC, Salel AF. Isradipine in the treatment of angina pectoris. American Journal of Medicine 84 (Suppl. 3B): 62–66, 1988Google Scholar
- Raemsch KD, Sommer J. Pharmacokinetics and metabolism of nifedipine. Hypertension 5 (Suppl. II): 18–24. 1983Google Scholar
- Rai GS, Murphy PJ. Whole blood viscosity and calcium blockers, isradipine and nifedipine in elderly hypertensives. Journal of Drug Development 1: 221–224, 1989Google Scholar
- Rauramaa R, Taskinen E, Seppänen K, Rissanen V, Salonen R, et al. Effects of calcium antagonist treatment on blood pressure, lipoproteins, and prostaglandins. American Journal of Medicine 84 (Suppl. 3B): 93–96, 1988Google Scholar
- Rowe JW. Approach to the treatment of hypertension in older patients. Preliminary results with isradipine. American Journal of Medicine 84 (Suppl. 3B): 46–50, 1988Google Scholar
- Rubin RP. The role of calcium in the release of neurotransmitter substances and hormones. Pharmacology Review 22: 389–428, 1970Google Scholar
- Ryan M, Jain A, Wallin D, Clifton G, McMahon FG, et al. Comparative effects of isradipine and enalapril on renal hemodynamics in essential hypertension. Abstract no. II-D-3. Clinical Pharmacology and Therapeutics 45: 160, 1989Google Scholar
- Sakanashi M, Noguchi K, Miyamoto Y, Kato T, Nagamine F, et al. Comparative effects of the calcium antagonist isradipine and some other dihydropyridine derivatives on regional blood flow in anesthetized open-chest dogs. Archives Internationales de Pharmacodynamic et de Therapie 294: 159–174, 1988bGoogle Scholar
- Sando H, Katagiri H, Okada M, Shoda R, Arai Y, et al. The effect of nifedipine and nicardipine on glucose tolerance, insulin and C-peptide. Abstract. Diabetes 32: 66A, 1983Google Scholar
- Scheidt S. The role of calcium blockers in the treatment of chronic stable angina. In Flaim SF & Zelis R (Eds) Calcium blockers: mechanisms of action and clinical applications, pp. 231–244, Urban & Schwarzenberg, Baltimore-Munich, 1982Google Scholar
- Scholtysik G, Schaad A. Cardiac cellular electrophysiology as a tool to prove Ca++ slow channel inhibition by PY 108-068. Triangle 21: 49–55, 1983Google Scholar
- Schran HF, Jaffe JM, Gonasun LM. Clinical pharmacokinetics of isradipine. American Journal of Medicine 84 (Suppl. 3B): 80–89, 1988Google Scholar
- Schran HF, Shepherd AM, Choc MM, Gonasun LM, Brodie CL. The effect of concomitant administration of isradipine and propranolol on their steady-state bioavailability. Abstract. Pharmacologist 31: 153, 1989Google Scholar
- Shaw AM, Brydon LJ, Maclntyre DE. PAF-induced human platelet aggregation is selectively inhibited by class II and class III, but not class I calcium ‘antagonists’. European Heart Journal 4 (Suppl. B): 4, 1983Google Scholar
- Shepherd AMM, Brodie CL, Carrillo DW, Kwan CM. Pharmacokinetic interaction between isradipine and propranolol. Abstract no. IVB-1, Clinical Pharmacology and Therapeutics 43: 194, 1988Google Scholar
- Shepherd AMM, Carr A, Davidoff M, Hamilton J, Schnaper H, et al. PN 200-110: gradual onset of antihypertensive action? Abstract no. PIID-4, Clinical Pharmacology and Therapeutics 41: 187, 1987Google Scholar
- Siejö BK. Cell damage in the brain: a speculative synthesis. Journal of Cerebral Blood Flow and Metabolism 1: 155–185, 1981Google Scholar
- Singh BN. Pharmacological basis for the therapeutic applications of slow-channel blocking drugs. Angiology-Journal of Vascular Diseases 33: 492–515, 1982Google Scholar
- Singh BN, Ellrodt G, Nademanee K. Calcium antagonists: cardiocirculatory effects and therapeutic applications. In Hurst JW (Ed.) Clinical Essays on the Heart, Vol. 2, pp. 65–97, McGraw-Hill, New York, 1984Google Scholar
- Smith SA, Young MA, Littler WA. Renal effects of nicardipine in essential hypertension. Abstract no. 41. Journal of Hypertension 5 (Suppl. 5): S640, 1987Google Scholar
- Sobel BE. Calcium antagonists in cardiovascular therapeutics. Practical Cardiology 7: 1–8, 1981Google Scholar
- Staessen J, Fagard R, Lijnen P, Amery A. Acute effects of isradipine on angiotensin II responsiveness. American Journal of Medicine 84 (Suppl. 3B): 67–71, 1988Google Scholar
- Stein GH, Lopez L, Quay G, McCarley D, Matthews K. Long-term improvement of lipid profiles with isradipine in elderly hypertensive patients. Abstract no. 1030. American Journal of Hypertension 2 (No. 5 Part 2): 8A, 1989Google Scholar
- Taira N. Effects of diltiazem and other calcium-antagonists on cardiac functions and coronary blood flow as assessed in blood-perfused dog-heart preparations. In Bing RJ (Ed.) New drug therapy with a calcium antagonist, Diltiazem Hakone Symposium ’78, pp. 91–103, Excerpta Medica, Amsterdam, 1979Google Scholar
- Taira N. Differences in cardiovascular profile among calcium antagonists. American Journal of Cardiology 59: 24B-29B, 1987Google Scholar
- Taylor SH, Jackson NC, Allen J, Pool PE. Efficacy of a new calcium antagonist PN 200-110 (isradipine) in angina pectoris. American Journal of Cardiology 59: 123B-129B, 1987Google Scholar
- Tse F, Jaffe J. Pharmacokinetics of PN 200-110 after single and repeated oral doses in man. Abstract no. 494. Acta Pharmacologica et Toxicologica 59 (Suppl. 5): 176, 1986Google Scholar
- Urien S, Pinquier J-L, Paquette B, Chaumet-Riffaud P, Kiechel J-R, et al. Effect of the binding of isradipine and darodipine to different plasma proteins on their transfer through the rat blood-brain barrier. Drug binding to lipoproteins does not limit the transfer of drug. Journal of Pharmacology and Experimental Therapeutics 242: 349–354, 1987PubMedGoogle Scholar
- van den Berg EK, Dehmer GJ. A comparison of the effects of intravenous isradipine and verapamil on coronary and systemic hemodynamics in man. Abstract. Journal of the American College of Cardiology 11: 242A, 1988bGoogle Scholar
- van den Toren EW, vanBruggen A, Ruegg PC, Lie KI. Hemodynamic effects of an intravenous infusion of isradipine in patients with congestive heart failure. American Journal of Medicine 84 (Suppl. 3B): 97–101, 1988Google Scholar
- Vermeulen A, Wester A, Willemse PFA, Lustermans FAT, Stegeman CJ, et al. Comparison of isradipine and diltiazem in the treatment of essential hypertension. American Journal of Medicine 84 (Suppl. 3B): 42–45, 1988Google Scholar
- Weinstein DB, Heider JG. Antiatherogenic properties of calcium antagonists. American Journal of Cardiology 59: 163B-172B, 1987Google Scholar
- Yasute H, Omote S, Takizawa A, Nagao M, Miwa K, et al. Exertional angina pectoris is caused by coronary arterial spasm: effects of various drugs. American Journal of Cardiology 43: 647–652, 1979Google Scholar